Modified forms of pharmacologically active agents and uses therefor

ABSTRACT

In accordance with the present invention, there are provided modified forms of nonsteroidal anti-inflamamatory drugs (NSAIDs). Modified NSAIDs according to the invention provide a new class of anti-inflammatory agent which provide the therapeutic benefits of NSAIDs while causing a much lower incidence of side-effects then typically observed with such agents.

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 10/097,197, filed Mar. 12, 2002, now pending, whichis a continuation of U.S. patent application Ser. No. 09/602,688, filedJun. 23, 2000, now issued as U.S. Pat. No. 6,355,666, and acontinuation-in-part of U.S. patent application 09/715,767, filed Nov.17, 2000, now issued as U.S. Pat. No. 6,429,223, the entire contents ofeach of which is hereby incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to novel forms of pharmacologicallyactive agents, and methods for the preparation and use thereof. In aparticular aspect of the invention, methods are provided for treatingpathological conditions with a modified form of one or morepharmacologically active agents, thereby reducing the occurrence ofside-effects caused thereby.

BACKGROUND OF THE INVENTION

[0003] Despite the advent of modem pharmaceutical technology, many drugsstill possess untoward toxicities which often limit the therapeuticpotential thereof. For example, although nonsteroid antiinflammatorydrugs (NSAIDs) are a class of compounds which are widely used for thetreatment of inflammation, pain and fever, NSAIDs (e.g., naproxen,aspirin, ibuprofen and ketoprofen) can cause gastrointestinal ulcers, aside effect that remains the major limitation to the use of NSAIDs (see,for example, J. L. Wallace, in Gastroenterol. 112:10001016 (1997); A. H.Soll et al., in Ann Intern Med. 114:307319 (1991); and J. Bjarnason etal., in Gastroenterol. 104:18321847 (1993)).

[0004] There are two major ulcerogenic effects of NSAIDs: (1) irritanteffects on the epithelium of the gastrointestinal tract and (2)suppression of gastrointestinal prostaglandin synthesis. In recentyears, numerous strategies have been attempted to design and develop newNSAIDs that reduce the damage to the gastrointestinal tract. Theseefforts, however, have largely been unsuccessful. For example, entericcoating or slow release formulations designed to reduce the topicalirritant properties of NSAIDs have been shown to be ineffective in termsof reducing the incidence of clinically significant side effects,including perforation and bleeding (see, for example, D. Y. Graham etal., in Clin. Pharmacol. Ther. 38:6570 (1985); and J. L. Carson, et al.,in Arch. Intern. Med., 147:10541059 (1987)).

[0005] It is well recognized that aspirin and other NSAIDs exert theirpharmacological effects through the non-selective inhibition ofcyclooxygenase (COX) enzymes, thereby blocking prostaglandin synthesis(see, for example, J. R. Van in Nature, 231:232235 (1971)). There aretwo types of COX enzymes, namely COX1 and COX2. COX1 is expressedconstitutively in many tissues, including the stomach, kidney, andplatelets, whereas COX2 is expressed only at the site of inflammation(see, for example, S. Kargan et al. in Gastroenterol., 111:445454(1996)). The prostagladins derived from COX1 are responsible for many ofthe physiological effects, including maintenance of gastric mucosalintegrity.

[0006] Many attempts have been made to develop NSAIDs that only inhibitCOX2, without impacting the activity of COX1 (see, for example, J. A.Mitchell et al., in Proc. Natl. Acad. Sci. USA 90:1169311697 (1993); andE. A. Meade et al., in J. Biol. Chem., 268:66106614 (1993)). There areseveral NSAIDs presently on the market (e.g., rofecoxib and celecoxib)that show marked selectivity for COX2 (see, for example, E. A. Meade,supra.; K. Glaser et al., in Eur. J. Pharmacol. 281:107111 (1995) andKaplan-Machlis, B., and Klostermeyer, B S in Ann Pharmacother.33:979-88, (1999)). These drugs appear to have reduced gastrointestinaltoxicity relative to other NSAIDs on the market.

[0007] On the basis of encouraging clinical as well as experimentaldata, the development of highly selective COX2 inhibitors appears to bea sound strategy to develop a new generation of antiinflammatory drugs.However, the physiological functions of COX1 and COX2 are not alwayswell defined. Thus, there is a possibility that prostagladins producedas a result of COX1 expression may also contribute to inflammation, painand fever. On the other hand, prostagladins produced by COX2 have beenshown to play important physiological functions, including theinitiation and maintenance of labor and in the regulation of boneresorption (see, for example, D. M. Slater et al., in Am. J. Obstet.Gynecol., 172:7782 (1995); and Y. Onoe et al., in J. Immunol. 156:758764(1996)), thus inhibition of this pathway may not always be beneficial.Considering these points, highly selective COX2 inhibitors may produceadditional side effects above and beyond those observed with standardNSAIDs, therefore such inhibitors may not be highly desirable.

[0008] Accordingly, there is still a need in the art for modified formsof NSAIDs which cause a reduced incidence of side-effects, relative tothe incidence of side-effects caused by such pharmacologically activeagents in unmodified form.

BRIEF DESCRIPTION OF THE INVENTION

[0009] In accordance with the present invention, there is provided a newclass of modified NSAIDs which cause a much lower incidence ofside-effects than are typically observed with unmodified NSAIDs due tothe protective effects imparted by modifying the NSAIDs as describedherein.

[0010] There are a number of advantages provided by modified NSAIDsaccording to the invention including one or more of the following:

[0011] (i) reduced irritant effects (e.g., contact irritation) ofNSAIDs,

[0012] (ii) enhanced tissue delivery of the drug as a result of adecrease in net charges on the molecule, particularly for acidic NSAIDssuch as naproxen, aspirin, diclofenac and ibuprofen, thereby reducingthe quantity of material which must be delivered to achieve an effectivedosage, and

[0013] (iii) reduction in the maximum concentration (C_(max)) achievedupon administration to a subject relative to the unmodified NSAID, whilemaintaining a therapeutically effective concentration of the NSAID inplasma of the subject.

[0014] In accordance with the present invention, cleavage of themodified NSAIDs described herein from the modified group appendedthereto releases the pharmaceutically active agent.

BRIEF DESCRIPTION OF THE FIGURES

[0015]FIG. 1 illustrates the total length of intestinal ulcers measuredafter three daily doses of NSAID in unfasted male Sprague-Dawley rats(150-200 g) treated with vehicle, naproxen, or equimolar inventioncomposition (compound 19). * P<0.05 by unpaired t-test.

[0016]FIG. 2 illustrates the total length of intestinal ulcers measuredafter 14 daily doses of NSAID in unfasted male Sprague-Dawley rats(150-200 g) treated with vehicle (bar 7), three doses of naproxen (bar1:50 mg/kg, bar 2:45 mg/kg, bar 3:40 mg/kg), or three equimolar doses ofinvention composition (compound 19) (bars 4-6). * P<0.05 by unpairedt-test vs. corresponding dose of naproxen.

[0017]FIG. 3 illustrates the inhibition of paw volume increases in theuninjected feet of Lewis male rats in which arthritis was induced byintradermal injection of adjuvant into the footpad. Rats were injectedon day 0 and treated once daily from days 8 to 15 with vehicle, naproxen(10 mg/kg), or invention composition (compound 19) at equivalent dose.Paw volumes were measured with a Plethysmometer on days 5 and 15. Closedcircles=naproxen; squares=invention composition.

[0018]FIG. 4 compares naproxen plasma concentration-time profiles (n=4,mean±s.d.) after oral administration of naproxen (darkened circles) at 2mg/kg and modified naproxen (open triangles) at an equivalent dose of 2mg/kg with respect to naproxen in rats. At predetermined times, bloodsamples were collected and centrifuged to obtain the plasma samples. Theplasma naproxen levels were measured by HPLC with a UV detection system.

DETAILED DESCRIPTION OF THE INVENTION

[0019] In accordance with the present invention, there are providedcompounds comprising a modified NSAID, wherein the NSAID is covalentlyattached either directly or through a linker molecule to asulfur-containing functional group. Exemplary invention compounds havethe structure:

X—L—Z

[0020] wherein:

[0021] X=a non-steroidal anti-inflammatory drug (NSAID),

[0022] L=an optional linker/spacer, and

[0023] Z=a sulfur-containing functional group.

[0024] NSAIDs contemplated for modification in accordance with thepresent invention include acetaminophen (Tylenol, Datril, etc.),aspirin, ibuprofen (Motrin, Advil, Rufen, others), choline magnesiumsalicylate (Triasate), choline salicylate (Anthropan), diclofenac(voltaren, cataflam), diflunisal (dolobid), etodolac (lodine),fenoprofen calcium (nalfon), flurbiprofen (ansaid), indomethacin(indocin, indometh, others), ketoprofen (orudis, oruvail), carprofen,indoprofen, ketorolac tromethamine (toradol), magnesium salicylate(Doan's, magan, mobidin, others), meclofenamate sodium (meclomen),mefenamic acid (relafan), oxaprozin (daypro), piroxicam (feldene),sodium salicylate, sulindac (clinoril), tolmetin (tolectin), meloxicam,nabumetone, naproxen, lomoxicam, nimesulide, indoprofen, remifenzone,salsalate, tiaprofenic acid, flosulide, and the like. Presentlypreferred NSAIDs employed in the practice of the invention includenaproxen, aspirin, ibuprofen, flurbiprofen, indomethacin, ketoprofen,carprofen, and the like. When the NSAID is aspirin, thesulfur-containing functional groups —CH₂S(O)₂CH₃, —CH₂S(O)CH₃, and —SCH₃are not presently preferred.

[0025] Invention compounds can be readily prepared in a variety of wayseither by direct reaction of NSAIDs with the sulfur-containingfunctional group or indirectly through a suitable linker molecule.

[0026] The components of invention compositions are directly orindirectly covalently attached employing a variety of linkages(including an optional linker), e.g., ester linkages, disulfidelinkages, amide linkages, immine linkages, enamine linkages, etherlinkages, thioether linkages, imide linkages, sulfate ester linkages,sulfonate ester linkages, sulfone linkages, sulfonamide linkages,phosphate ester linkages, carbonate linkages, O-glycosidic linkages,S-glycosidic linkages, and the like. Such linkages can be accomplishedusing standard synthetic techniques as are well known by those of skillin the art, either by direct reaction of the starting materials, or byincorporating a suitable functional group on the starting material,followed by coupling of the reactants.

[0027] When the NSAIDs contemplated for use herein contain suitablefunctionality thereon, e.g., hydroxy, amino, carboxy, and the like,invention modified NSAIDs can be prepared by direct linkage between theNSAID and the sulfur-containing functional group. Alternatively, theNSAIDs can be functionalized so as to facilitate linkage between theNSAID and the sulfur-containing functional group. When present,linker/spacer L has the following structure:

—W—R—

[0028] wherein:

[0029] R is optional, and when present is alkylene, substitutedalkylene, cycloalkylene, substituted cycloalkylene, heterocyclic,substituted heterocyclic, oxyalkylene, substituted oxyalkylene,alkenylene, substituted alkenylene, arylene, substituted arylene,alkarylene, substituted alkarylene, aralkylene or substitutedaralkylene, and

[0030] W is ester, reverse ester, thioester, reverse thioester, amide,reverse amide, phosphate, phosphonate, imine, enamine, hydroxymate, orthe like.

[0031] Functional groups contemplated by the present invention aresulfur-based. Examples of suitable sulfur-containing functional groupsinclude sulfonate, reverse sulfonate, sulfonamide, reverse sulfonamide,sulfone, sulfoxide, sulfinate, reverse sulfinate, and the like. In aparticular aspect of the invention, the sulfur-based moiety is sulfonateor reverse sulfonate. In a particularly preferred aspect of theinvention, the sulfonate is an optionally substituted aromatic sulfonatesuch as tosylate or brosylate.

[0032] Other preferred sulfur-based functional groups contemplated bythe present invention include sulfones. Preferably, the sulfone is anoptionally substituted alkyl or aromatic sulfone.

[0033] In one aspect of the invention, Z may have the followingstructure:

—Y—S(O)n—Y′—Q

[0034] wherein:

[0035] each of Y and Y′ are optionally present, and when present areindependently —O—, —S— or —NR′—, wherein R′ is H or an optionallysubstituted hydrocarbyl moiety;

[0036] n is 1 or 2, and

[0037] Q is H, a metal cation or an optionally substituted hydrocarbylmoiety.

[0038] As employed herein, “hydrocarbyl” embraces alkyl, substitutedalkyl, oxyalkyl, substituted oxyalkyl, cycloalkyl, substitutedcycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,monocyclic heterocylic, substituted monocyclic heterocyclic, monocyclicaromatic, monosubstituted monocyclic aromatic, or the like.

[0039] As employed herein, “alkyl” refers to hydrocarbyl radicals having1 up to 20 carbon atoms, preferably 2-10 carbon atoms; and “substitutedalkyl” comprises alkyl groups further bearing one or more substituentsselected from hydroxy, alkoxy (of a lower alkyl group), mercapto (of alower alkyl group), cycloalkyl, substituted cycloalkyl, heterocyclic,substituted heterocyclic, aryl, substituted aryl, heteroaryl,substituted heteroaryl, aryloxy, substituted aryloxy, halogen,trifluoromethyl, cyano, nitro, nitrosothiol (—SNO), nitrate (i.e.,nitrous acid ester), nitrone, nitrite (i.e., nitric acid ester),nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime,N-hydroxylguanidinyl, amino, amido, —C(O)H, acyl, oxyacyl, carboxyl,carbamate, sulfonyl, sulfinyl, sulfonamide, sulfuryl, and the like.

[0040] As employed herein, “oxyalkyl” refers to the moiety —O-alkyl-,wherein alkyl is as defined above, and “substituted oxyalkyl” refers tooxyalkyl groups further bearing one or more substituents as set forthabove.

[0041] As employed herein, “cycloalkyl” refers to cyclic ring-containinggroups containing in the range of about 3 up to 8 carbon atoms, and“substituted cycloalkyl” refers to cycloalkyl groups further bearing oneor more substituents as set forth above.

[0042] As employed herein, “heterocyclic” refers to cyclic (i.e.,ring-containing) groups containing one or more heteroatoms (e.g., N, O,S, or the like) as part of the ring structure, and having in the rangeof 3 up to 14 carbon atoms and “substituted heterocyclic” refers toheterocyclic groups further bearing one or more substituents as setforth above.

[0043] As employed herein, “alkenyl” refers to straight or branchedchain hydrocarbyl groups having at least one carbon-carbon double bond,and having in the range of about 2 up to 12 carbon atoms, and“substituted alkenyl” refers to alkenyl groups further bearing one ormore substituents as set forth above.

[0044] As employed herein, “alkynyl” refers to straight or branchedchain hydrocarbyl groups having at least one carbon-carbon triple bond,and having in the range of about 2 up to 12 carbon atoms, and“substituted alkynyl” refers to alkynylene groups further bearing one ormore substituents as set forth above.

[0045] As employed herein, “monocyclic aromatic” refers to aromaticgroups having in the range of 5 up to 7 carbon atoms and“monosubstituted monocyclic aromatic” refers to aromatic groups furtherbearing one of the substituents set forth above.

[0046] As employed herein, “alkylene” refers to divalent hydrocarbylradicals having 1 up to 20 carbon atoms, preferably 2-10 carbon atoms;and “substituted alkylene” comprises alkylene groups further bearing oneor more substituents as set forth above.

[0047] As employed herein, “cycloalkylene” refers to cyclicring-containing groups containing in the range of about 3 up to 8 carbonatoms, and “substituted cycloalkylene” refers to cycloalkylene groupsfurther bearing one or more substituents as set forth above.

[0048] As employed herein, “oxyalkylene” refers to the moiety—O-alkylene-, wherein alkylene is as defined above, and “substitutedoxyalkylene” refers to oxyalkylene groups further bearing one or moresubstituents as set forth above.

[0049] As employed herein, “alkenylene” refers to divalent, straight orbranched chain hydrocarbyl groups having at least one carbon-carbondouble bond, and having in the range of about 2 up to 12 carbon atoms,and “substituted alkenylene” refers to alkenylene groups further bearingone or more substituents as set forth above.

[0050] As employed herein, “alkynylene” refers to divalent straight orbranched chain hydrocarbyl groups having at least one carbon-carbontriple bond, and having in the range of about 2 up to 12 carbon atoms,and “substituted alkynylene” refers to alkynylene groups further bearingone or more substituents as set forth above.

[0051] As employed herein, “arylene” refers to divalent aromatic groupshaving in the range of 6 up to 14 carbon atoms and “substituted arylene”refers to arylene groups further bearing one or more substituents as setforth above.

[0052] As employed herein, “alkylarylene” refers to alkyl-substitutedarylene groups and “substituted alkylarylene” refers to alkylarylenegroups further bearing one or more substituents as set forth above.

[0053] As employed herein, “arylalkylene” refers to aryl-substitutedalkylene groups and “substituted arylalkylene” refers to arylalkylenegroups further bearing one or more substituents as set forth above.

[0054] As employed herein, “arylalkenylene” refers to aryl-substitutedalkenylene groups and “substituted arylalkenylene” refers toarylalkenylene groups further bearing one or more substituents as setforth above.

[0055] As employed herein, “arylalkynylene” refers to aryl-substitutedalkynylene groups and “substituted arylalkynylene” refers toarylalkynylene groups further bearing one or more substituents as setforth above.

[0056] Diseases and conditions contemplated for treatment in accordancewith the present invention include inflammatory and infectious diseases,such as, for example, septic shock, hemorrhagic shock, anaphylacticshock, toxic shock syndrome, ischemia, cerebral ischemia, administrationof cytokines, overexpression of cytokines, ulcers, inflammatory boweldisease (e.g., ulcerative colitis or Crohn's disease), diabetes,arthritis (e.g., rheumatoid athritis and osteoarthritis), asthma,Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis,allograft rejection, encephalomyelitis, meningitis, pancreatitis,peritonitis, vasculitis, lymphocytic choriomeningitis,glomerulonephritis, uveitis, ileitis, inflammation (e.g., liverinflammation, renal inflammation, and the like), burn, infection(including bacterial, viral, fungal and parasitic infections),hemodialysis, chronic fatigue syndrome, stroke, cancers (e.g., breast,melanoma, carcinoma, and the like), cardiopulmonary bypass,ischemic/reperfusion injury, gastritis, adult respiratory distresssyndrome, cachexia, myocarditis, autoimmune disorders, eczema,psoriasis, heart failure, heart disease, atherosclerosis, dermatitis,urticaria, systemic lupus erythematosus, AIDS, AIDS dementia, chronicneurodegenerative disease, pain (e.g., chronic pain and post-surgicalpain), priapism, cystic fibrosis, amyotrophic lateral sclerosis,schizophrenia, depression, premenstrual syndrome, anxiety, addiction,headache, migraine, Huntington's disease, epilepsy, neurodegencrativedisorders, gastrointestinal motility disorders, obesity, hyperphagia,solid tumors (e.g., neuroblastoma), malaria, hematologic cancers,myelofibrosis, lung injury, graftversushost disease, head injury, CNStrauma, hepatitis, renal failure, liver disease (e.g., chronic hepatitisC), drug-induced lung injury (e.g., paraquat), myasthenia gravis (MG),ophthalmic diseases, postangioplasty, restenosis, angina, coronaryartery disease, and the like.

[0057] In accordance with another embodiment of the present invention,there are provided methods for the preparation of modified NSAIDs, saidmethod comprising covalently attaching a NSAID to a sulfur-containingfunctional group. The resulting compound provides a latent form of thepharmacologically active agent, releasing the biological activitythereof only when the compound is cleaved (e.g., by an esterase, amidaseor other suitable enzyme).

[0058] As readily recognized by those of skill in the art, inventioncompounds can be prepared in a variety of ways. See, for example,Schemes 1A and 1B, wherein NSAID, X, bearing a carboxylic moiety can bereacted either directly with the sulfur-containing functional group(Scheme 1A) or indirectly through a linker molecule (Scheme 1B).

[0059] Employing these general reaction schemes, invention modifiedNSAIDs can be prepared from a wide variety of pharmacologically activeagents. See, for example, Examples 1-59 provided herein.

[0060] In accordance with yet another embodiment of the presentinvention, there are provided methods for reducing the side effectsinduced by administration of NSAIDs to a subject, said method comprisingreducing the C_(max) relative to unmodified NSAIDs while maintaining atherapeutically effective concentration in plasma upon administration toa subject in need thereof. The reduction in C_(max) is achieved, forexample, by covalently attaching a sulfur-containing functional groupcontaining an optionally substituted hydrocarbyl moiety to said NSAIDprior to administration to said subject, as depicted in Schemes 1A and1B.

[0061] In a particular embodiment of the invention, the C_(max) isreduced relative to the unmodified NSAID by about 10% to 90%. In apresently preferred embodiment, the C_(max) is reduced relative to theunmodified NSAID by about 20% to 80%. In a most preferred embodiment,the C_(max) is reduced relative to the unmodified NSAID by about 40% to70%.

[0062] In accordance with still another embodiment of the presentinvention, there are provided methods for enhancing the effectiveness ofNSAIDs, said method comprising reducing the C_(max) relative tounmodified NSAIDs while maintaining a therapeutically effectiveconcentration in plasma upon administration to a subject in needthereof. The enhanced effectiveness of said NSAIDs is achieved, forexample, by covalently attaching a sulfur-containing functional groupcontaining an optionally substituted hydrocarbyl moiety to said NSAID.

[0063] In accordance with a still further embodiment of the presentinvention, there are provided improved methods for the administration ofNSAIDs to a subject for the treatment of a pathological condition, theimprovement comprising reducing the C_(max) relative to unmodifiedNSAIDs while maintaining a therapeutically effective concentration inplasma upon administration to a subject in need thereof. The improvementis accomplished, for example, by covalently attaching said NSAID to asulfur-containing functional group containing an optionally substitutedhydrocarbyl moiety prior to administration thereof to said subject.

[0064] Those of skill in the art recognize that the modified NSAIDsdescribed herein can be delivered in a variety of ways, such as, forexample, orally, intravenously, subcutaneously, parenterally, rectally,by inhalation, and the like.

[0065] Depending on the mode of delivery employed, the modified NSAIDscontemplated for use herein can be delivered in a variety ofpharmaceutically acceptable forms. For example, the invention modifiedNSAIDs can be delivered in the form of a solid, solution, emulsion,dispersion, micelle, liposome, and the like.

[0066] Thus, in accordance with still another embodiment of the presentinvention, there are provided physiologically active composition(s)comprising invention modified NSAIDs in a suitable vehicle renderingsaid compounds amenable to oral delivery, transdermal delivery,intravenous delivery, intramuscular delivery, topical delivery, nasaldelivery, and the like.

[0067] Pharmaceutical compositions of the present invention can be usedin the form of a solid, a solution, an emulsion, a dispersion, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more of the modified NSAIDs of the present invention, asan active ingredient, in admixture with an organic or inorganic carrieror excipient suitable for enteral or parenteral applications. Inventionmodified NSAIDs may be compounded, for example, with the usualnon-toxic, pharmaceutically acceptable carriers for tablets, pellets,capsules, suppositories, solutions, emulsions, suspensions, and anyother form suitable for use. The carriers which can be used includeglucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventionmodified NSAIDs are included in the pharmaceutical composition in anamount sufficient to produce the desired effect upon the process ordisease condition.

[0068] Pharmaceutical compositions containing invention modified NSAIDsmay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of a sweetening agent such assucrose, lactose, or saccharin, flavoring agents such as peppermint, oilof wintergreen or cherry, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontaining inventon modified NSAIDs in admixture with non-toxicpharmaceutically acceptable excipients may also be manufactured by knownmethods. The excipients used may be, for example, (1) inert diluentssuch as calcium carbonate, lactose, calcium phosphate or sodiumphosphate; (2) granulating and disintegrating agents such as cornstarch, potato starch or alginic acid; (3) binding agents such as gumtragacanth, corn starch, gelatin or acacia, and (4) lubricating agentssuch as magnesium stearate, stearic acid or talc. The tablets may beuncoated or they may be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate maybe employed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotictherapeutic tablets for controlled release.

[0069] In some cases, formulations for oral use may be in the form ofhard gelatin capsules wherein the invention modified NSAIDs are mixedwith an inert solid diluent, for example, calcium carbonate, calciumphosphate or kaolin. They may also be in the form of soft gelatincapsules wherein the invention modified NSAIDs are mixed with water oran oil medium, for example, peanut oil, liquid paraffin, or olive oil.

[0070] The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

[0071] Invention modified NSAIDs contemplated for use in the practice ofthe present invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention modified NSAIDs with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquify and/or dissolve in the rectal cavity torelease the drug.

[0072] Since individual subjects may present a wide variation inseverity of symptoms and each drug has its unique therapeuticcharacteristics, the precise mode of administration and dosage employedfor each subject is left to the discretion of the practitioner.

[0073] In general, the dosage of invention modified NSAIDs employed asdescribed herein falls in the range of about 0.01 mmoles/kg body weightof the subject/hour up to about 0.5 mmoles/kg/hr. Typical daily doses,in general, lie within the range of from about 10 μg up to about 100 mgper kg body weight, and, preferably within the range of from 50 μg to 10mg per kg body weight and can be administered up to four times daily.The daily IV dose lies within the range of from about 1 μg to about 100mg per kg body weight, and, preferably, within the range of from 10 μgto 10 mg per kg body weight.

[0074] In accordance with yet another embodiment of the presentinvention, there are provided improved methods for the treatment of asubject suffering from a pathological condition by administrationthereto of a NSAID, the improvement comprising reducing the C_(max)relative to unmodified NSAIDs while maintaining a therapeuticallyeffective concentration in plasma upon administration to a subject inneed thereof. The improvement is achieved, for example, by covalentlyattaching said NSAID to a sulfur-containing functional group prior toadministration thereof to said subject.

[0075] Thus, invention method for the treatment of a subject afflictedwith a pathological condition comprises administering to a subject aneffective amount of a modified pharmacologically active agent,

[0076] wherein said pharmacologically active agent is a NSAID, and iseffective for treatment of said condition, and

[0077] wherein said pharmacologically active agent has been modified toreduce the C_(max) relative to unmodified NSAIDs while maintaining atherapeutically effective concentration in plasma upon administration toa subject in need thereof. The modification is accomplished, forexample, by the covalent attachment to the NSAID of a sulfur-containingfunctional group.

[0078] The invention will now be described in greater detail byreference to the following non-limiting examples.

[0079] The syntheses described in Examples 1-8 are outlined in Scheme 2.

EXAMPLE 1

[0080] Compound 10 (Scheme 2). A mixture of Naproxen (1) (23 g, 0.1mol), ethylene glycol (2) (27.9 ml, 0.5 mol) and toluenesulfonic acid(TsOH) (1.27 g, 6.7 mmol) in CHCl₃ was heated to reflux for 4 h. Thereaction solution was washed with water, 10% Na₂CO₃ solution and water.The organic layer was dried (Na₂SO₄) and the solvent was evaporated. Theresidue was purified by crystallization from CH₂Cl₂ and hexanes to give25.7 g (94%) of the compound 10 as a white crystal; ¹H NMR (CDCl₃) δ1.59(d, 3H), 1.62 (br, 1H, ex D₂O), 3.74 (t, 2H), 3.90 (q, 1H), 3.91 (s,3H), 4.21 (t, 2H), 7.11 (m, 2H), 7.39 (d, 1H), 7.69 (m, 3H); ¹³C NMR(CDCl₃) δ18.7, 45.6, 55.5, 61.4, 66.6, 105.8, 119.3, 126.1, 126.2,127.5, 129.1, 129.5, 133.9, 135.7, 157.9, 175.2; MS (ESI) m/z 273 (M−1).

[0081] Compound 18 (Scheme 2). To a solution of compound 10 (24.5 g, 89mmol) in 100 ml of pyridine was added tosyl chloride (TsCl) (34.1 g, 179mmol). The resulting solution was stirred at 0° C. for 2.5 h. Thereaction solution was then poured into 300 ml of water and then 200 mlof ether was added. The layers were separated and the organic phase waswashed with water (300×5) and dried (Na₂SO₄). After the solvent wasevaporated, the residue was purified by column chromatography on asilica gel column using dichloromethane as an eluent to give 35.1 g(92%) of the pale yellow oil; ¹H NMR (CDCl₃) δ1.55(d, 3H), 2.40 (s, 3H),3.91 (q, 1H), 4.18 (m, 4H), 7.12 (m, 2H), 7.24 (m, 2H), 7.37 (d, 1H),7.66 (d, 1H), 7.70 (m, 4H); MS (ESI) m/z 429 (M+1).

EXAMPLE 2

[0082] Compound 11 (Scheme 2). Compound 11 was prepared as describedabove for the preparation of compound 10, this time employing naproxen(1) and 1,3-propanediol (3). The resulting compound 11 was purified bycrystallization from dichloromethane and hexanes with a 92% yield. ¹HNMR (CDCl₃) δ1.59 (d, 3H), 1.78 (m, 2H), 1.87 (br, 1H, D₂O ex), 3.53 (t,2H), 3.87 (q, 1H), 3.91 (s, 3H), 4.23 (t, 2H), 7.11 (d, 1H), 7.15 (m,1H), 7.41 (q, 1H), 7.66 (d, 1H), 7.69 (s, 1H), 7.71 (s, 1H); ¹³C NMR(CDCl₃) δ18.6, 31.8, 45.7, 55.5, 59.2, 61.9, 77.0, 77.2, 77.5, 105.8,119.2, 126.1, 126.3, 127.4, 129.1, 129.4, 133.9, 135.7, 157.8, 175.3;and MS (ESI) m/z 289.4 (M+1).

[0083] Compound 19 (Scheme 2). Compound 19 was prepared as describedabove for the preparation of compound 18, this time employing compound11 and TsCl. Compound 19 was purified by crystallization from ether andhexane with an yield of 95%; ¹H NMR (CDCl₃) δ1.54 (d, 3H), 1.91 (m, 2H),2.42 (s, 3H), 3.79 (q, 1H), 3.92 (s, 3H), 3.99 (t, 2H), 4.10 (t, 2H),7.11 d, 1H), 7.15 (q, 1H), 7.26 (d, 2H), 7.34 (d, 2H), 7.62(d, 1H), 7.70(m, 4H); ¹³C NMR (CDCl₃) δ18.5, 21.8, 28.4, 45.5, 55.5, 60.6, 66.9,105.8, 119.2, 126.0, 126.3, 127.4, 128.0, 129.1, 129.5, 130.1, 133.1,133.9, 135.6, 145.0, 157.9, 174.5; MS (ESI) m/z 421.1 (M−1).

EXAMPLE 3

[0084] Compound 12 (Scheme 2). Compound 12 was prepared as describedabove for the preparation of compound 10, this time employing naproxen(1) and 1,4-butanediol (4). Compound 12 was purified by crystallizationfrom dichloromethane and hexanes with a 90% yield; ¹H NMR (CDCl₃) δ1.48(m, 2H), 1.59 (d, 3H), 1.64 (m, 2H), 1.85 (s, 1H, D₂O, ex), 3.52 (t,2H), 3.85 (q, 1H), 3.89 (s, 3H), 4.10 (t, 2H), 7.10-7.15 (m, 2H), 7.42(, d, 1H), 7.66-7.7-(m, 3H); MS (ESI) m/z 325.4 (M+Na).

[0085] Compound 20 (Scheme 2). Compound 20 was prepared as describedabove for the preparation of compound 18, this time employing compound12 and TsCl. The compound 20 was purified by crystallization from etherand hexane with an yield of 93%; ¹H NMR (CDCl₃) δ1.55 (d, 3H), 1.53-1.62(m, 4H), 2.43 (s, 3H), 3.82 (q, 1H), 3.92 (s, 3H), 3.94 (m, 2H), 4.02(m, 2H), 7.11-7.15 (m, 2H), 7.30 (d, 2h), 7.38 (d, 1H), 7.64 (d, 1H),7.70 (d, 2H), 7.75 (d, 2H); MS (ESI) m/z 457.5 (M+1).

EXAMPLE 4

[0086] Compound 13 (Scheme 2). Compound 13 was prepared as describedabove for the preparation of compound 10, this time employing naproxen(1) and 1,5-pentanediol (5). After reaction, the reaction solution waswashed with water and the reaction solvent was then evaporated underhigh vaccum to give a quantitative yield of the compound 13. Thecompound was used to make compound 21 without further purification; ¹HNMR (CDCl₃) δ1.28 (m, 2H), 1.46 (m, 2H), 1.55 (d, 3H), 1.59 (m, 2H),3.51 (t, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.09 (t, 2H), 7.11-7.15 (m,2H), 7.40 (q, 1H), 7.66-7.70 (m, 3H); MS (ESI) m/z 317.5 (M+1).

[0087] Compound 21 (Scheme 2). Compound 21 was prepared as describedabove for the preparation of compound 18, this time employing compound13 and TsCl. Compound 21 was purified by crystallization from ether andhexane with a 95% yield; ¹H NMR (CDCl₃) δ1.24 (m, 2H), 1.48-1.58 (m,4H), 1.59 (d, 3H), 2.43 (s, 3H), 3.84 (q, 1H), 3.89 (t, 2H), 3.91 (s,3H), 4.01 (t, 2H),7.11-7.15 (m, 2H), 7.32 (q, 2H), 7.39 (q, 1H), 7.65(d, 1H), 7.70 (m, 2H), 7.75 (d, 2H); MS (ESI) m/z 471.7 (M+1).

EXAMPLE 5

[0088] Compound 14 (Scheme 2). Compound 14 was prepared as describedabove for the preparation of compound 10, this time employing naproxen(1) and 1,6-hexanediol (6). After reaction, the reaction solution waswashed with water and the reaction solvent was then evaporated to givecompound 14 as a solid. The compound was used to make compound 22without further purification; ¹H NMR (CDCl₃) δ1.24 (m, 4H), 1.43 (m 2H),1.56 (d, 3H), 1.54 (m, 2H), 3.51 (t, 2H), 3.85 (q, 1H), 4.01 (m, 2H),7.10-7.15 (m 2H), 7.40 (q, 1H), 7.66-7.70 (m, 3H); MS (ESI) m/z 331.7(M+1).

[0089] Compound 22 (Scheme 2). Compound 22 was prepared as describedabove for the preparation of compound 18, this time employing compound14 and TsCl. Compound 22 was purified by column chromatography on asilica gel column using dichloromethane as an eluent to give compound 22as a pale yellow oil; ¹H NMR (CDCl₃) δ1.12-1.22 (m, 4H), 1.46-1.52 (m,4H), 1.57 (d, 3H), 2.43 (s, 3H), 3.84 (q, 1H), 3.92 (s, 3H), 3.93 (m,2H), 4.03 (m, 2H), 7.11-7.77 (m, 10H); MS (ESI) m/z 485.6 (M+1).

EXAMPLE 6

[0090] Compound 15 (Scheme 2). Compound 15 was prepared as describedabove for the preparation of compound 10, this time employing naproxen(1) and di(ethylene glycol) (7). After reaction, the reaction solutionwas washed with water and the reaction solvent was then evaporated togive compound 15. The compound was used to make compound 23 withoutfurther purification; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 1.93 (br, 1H, D₂Oex), 3.43 (t, 2H), 3.59 (t, 2H), 3.62 (t, 2H), 3.89 (q, 1H), 3.90 (s,3H), 4.25 (m, 2H), 7.11-7.15 (m, 2H), 7.40-7.42 (m, 1H), 7.70 (t, 3H);¹³C NMR (CDCl₃) δ18.7, 45.6, 55.5, 61.8, 64.0, 69.2, 72.4, 76.9, 77.2,77.5, 105,7, 119.2, 126.2, 126.4, 127.3, 129.0, 133.9, 135.7, 157.9,174.8; MS(ESI) m/z 319.3 (M+1).

[0091] Compound 23 (Scheme 2). Compound 23 was prepared as describedabove for the preparation of compound 18, this time employing compound15 and TsCl. Compound 23 was purified by column chromatography on asilica gel column using dichloromethane as an eluent to give thecompound as a pale yellow oil with a 93% yield. ¹H NMR (CDCl₃) δ1.58 (d,3H), 2.41 (s, 3H), 3.43 (m, 2H), 3.48(m, 2H), 3.84 (q, 1H), 3.86 (s,3H), 3.94 (t, 2H), 4.10 (m, 2H), 7.10-7.13 (m, 2H), 7.29 (d, 2H), 7.39(d, 1H), 7.65-7.75 (m, 5H); ¹³C NMR (CDCl₃) δ18.6, 21.8, 45.5, 55.5,63.9, 68.7, 69.27, 69.27, 105.8, 119.2, 126.2, 126.4, 127.4, 128.1,129.0, 129.4, 129.9, 133.9, 145.0, 157.9, 174.7; MS (ESI) m/z 473.4(M+1).

EXAMPLE 7

[0092] Compound 16 (Scheme 2). Compound 16 was prepared as describedabove for the preparation of compound 10, this time employing naproxen(1) and 1,3-pentanediol (8). After reaction, the reaction solution waswashed with water and the reaction solvent was then evaporated to givecompound 15 with a 32% yield. The compound was used to make compound 24without further purification; ¹H NMR, ¹³C NMR and MS are consistent withthe structure of compound 16.

[0093] Compound 24 (Scheme 2). Compound 24 was prepared as describedabove for the preparation of compound 18, this time employing compound16 and TsCl. The compound 24 was purified by column chromatography on asilica gel column using dichloromethane as an eluent to give thecompound as a pale yellow oil with a 82% yield. The ¹H NMR, ¹³C NMR andMS are consistent with the structure of compound 24.

EXAMPLE 8

[0094] Compound 17 (Scheme 2). Compound 17 was prepared as describedabove for the preparation of compound 10, this time employing naproxen(1) and 1,4-cyclohexanediol (8). After reaction, the reaction solutionwas washed with water and the reaction solvent was then evaporated togive compound 17. Compound 17 was used to make compound 25 withoutfurther purification; ¹H NMR (CDCl₃) δ1.30-1.45 (m, 6H), 1.56 (d, 3H),1.80-1.98 (m, 4H), 3.66 (m, 1H), 3.82 (q, 1H), 3.91 (s, 3H), 4.75 (m,1H), 7.11 m, 2H), 7.39 (d, 1H), 7.65-7.70 (m, 3H); ¹³C NMR (CDCl₃)δ18.7, 28.2, 28.5, 32.1, 32.2, 45.9, 55.5, 68.9, 72.0, 76.9, 77.2, 77.5,105.8, 119.1, 126.0, 126.4, 127.2, 129.1, 129.5, 133.8, 136.1, 157.8,174.4; MS (ESI) m/z 351.4 (M+Na).

[0095] Compound 25 (Scheme 2). Compound 25 was prepared as describedabove for the preparation of compound 18, this time employing compound17 and TsCl. Compound 25 was purified by column chromatography on asilica gel column using dichloromethane as an eluent to give thecompound as a pale yellow oil with a 93% yield; ¹H NMR (CDCl₃)δ1.50-1.84 (m, 11H), 2.43 (s, 3H), 3.80 (q, 1H), 3.92 (s, 3H), 4.51 (m,1H), 4.78 (m, 1H), 7.10-7.15 (m 2H), 7.26-7.39 (m, 3H), 7.61-7.75 (m,5H); MS (ESI) m/z 483.5 (M+H).

[0096] The syntheses described in Examples 9-14 are outlined in Scheme3.

EXAMPLE 9

[0097] Compound 32 (Scheme 3). Compound 32 was prepared as describedabove for the preparation of compound 10, this time employing ketoprofen(26) and 1,3-propanediol (3). Compound 32 was purified by columnchromatography on a silica gel column using 200:1 CH₂Cl₂/MeOH as aneluent to give compound 32 with a 50% yield. ¹H NMR (CDCl₃) δ1.55 (d,3H), 1.82 (m 3H, 1H, D₂O ex), 3.58 (m, 2H), 3.82(m, 1H), 4.25 (m 2H),7.44-7.82 (m, 9H); MS (ESI) m/z 313.5 (M+H).

[0098] Compound 38 (Scheme 3). Compound 38 was prepared as describedabove for the preparation of compound 18, this time employing compound32 and TsCl. Compound 38 was purified by column chromatography on asilica gel column using CH₂Cl₂ as an eluent to give the compound 38 as acolorless oil with a 81% yield; ¹H NMR (CDCl₃) δ1.49 (d, 3H), 1.94 (m,2H), 2.43 (s, 3H), 3.72 (q, 1H), 4.01 (t, 2H), 4.12 (m, 2H), 7.31-7.78(m, 13H); MS (ESI) m/z 467.3 (M+H).

EXAMPLE 10

[0099] Compound 33 (Scheme 3). Compound 33 was prepared as describedabove for the preparation of compound 10, this time employingflurbiprofen (27) and 1,3-propanediol (3). After reaction, the reactionsolution was washed in water and the reaction solvent was thenevaporated to give the compound 33 with a quantitative yield. Thecompound 33 was used to make compound 39 without further purification;¹H NMR (CDCl₃) δ1.54 (d, 3H), 1.79 (t, 1H, D₂O ex), 1.85 (m, 2H), 3.63(m, 2H), 3.76 (q, 1H), 4.27 (t, 2H), 7.11-7.16(m, 2H), 7.35-7.46 (m,4H), 7.54 (d, 2H); MS (ESI) m/z 325.4 (M+Na).

[0100] Compound 39 (Scheme 3). Compound 39 was prepared as describedabove for the preparation of compound 18, this time employing compound33 and TsCl. Compound 39 was purified by crystallization fromether/hexane system with a 79% yield; ¹H NMR (CDCl₃) δ1.50 (d, 3H), 1.96(m, 2H), 2.42 (s, 3H), 3.68 (q, 1H), 4.03 (t, 2H), 4.15 (t, 2H),7.05-7.11 (m, 2H), 7.25-7.54 (m, 8H), 7.76 (d, 2H); ¹³C NMR (CDCl³)δ18.4, 21.8, 28.4, 45.0, 50.8, 66.9, 115.2, 115.5, 123.68, 123.7, 127.9,128.0, 129.2, 130.1, 131.0, 133.1, 135.6, 141.75, 141.8, 145.1, 158.9,160.9, 173.9; MS (ESI) m/z 479.4 (M+Na).

EXAMPLE 11

[0101] Compound 34 (Scheme 3). Compound 34 was prepared as describedabove for the preparation of compound 10, this time employing ibuprofen(28) and 1,3-propanediol (3). After reaction, the reaction solution waswashed in water and the reaction solvent was then evaporated to givecompound 34 with a quantitative yield. The compound 34 was used to makecompound 40 without further purification; ¹H NMR (CDCl₃) δ0.89 (d, 6H),1.49 (d, 3H), 1.79 (t, 2H), 1.78-1.85 (m, 1H), 1.95 (t, 1H, D₂O ex),2.45 (d, 2H), 3.53 (m, 2H), 3.71 (q, 1H), 4.22 (m, 2H), 7.09 (d, 2H),7.26 (d, 2H).

[0102] Compound 40 (Scheme 3). Compound 40 was prepared as describedabove for the preparation of compound 18, this time employing compound34 and TsCl. Compound 40 was purified by crystallization fromether/hexane system to give a white solid with a 96% yield; ¹H NMR(CDCl₃) δ0.89 (d, 6H), 1.44 (d, 3H), 1.81-1.92 (m, 3H), 2.44 (s, 3H),3.61 (q, 1H), 3.99 (t, 2H), 4.09 (t, 2H), 7.08 (d, 2H), 7.14 (d, 2H),7.34 (d, 2H), 7.78 (d, 2H); ¹³C NMR (CDCl₃) δ18.46, 21.80, 22.54, 28.39,30.32, 45.16, 60.39, 66.92, 127.23, 128.04, 129.50, 130.03, 133.12,137.68, 140.76, 145.00, 174.54; MS (ESI) m/z 441.5 (M+Na).

EXAMPLE 12

[0103] Compound 35 (Scheme 3). Compound 35 was prepared as describedabove for the preparation of compound 10, this time employing diclofenac(29) and 1,3-propanediol (3). After reaction, compound 35 was purifiedby column chromatography on a silica gel column using 200:1 CH₂Cl₂/MeOHas an eluent to give the compound 35 as a white solid with a 56% yield.¹H NMR (CDCl₃) δ1.89 (m, 3H, 1H D₂O ex), 3.66 (t, 2H), 3.83 (s, 3H),4.31 (t, 2H), 6.55 (d, 1H), 6.87 (br, 1H), 6.94-7.00 (m, 2H), 7.11-7.14(m, 1H), 7.22-7.26 (m, 1H), 7.34 (d, 2H); MS (ESI) m/z 376.3 (M+Na).

[0104] Compound 41 (Scheme 3). Compound 41 was prepared as describedabove for the preparation of compound 18, this time employing compound35 and TsCl. Compound 41 was purified by column chromatography on asilica gel column using CH₂Cl₂ as an eluent to give the compound 41 as apale yellow oil and the yield was 89%; ¹H NMR (CDCl₃) δ2.02 (m, 2H),2.43 (s, 3H), 3.73 (s, 2H), 4.09 (t, 2H), 4.17 (t, 2H), 6.53 (d, 1H),6.99 (s, 1H), 6.93-7.00 (m, 2H), 7.12 (t, 1H), 7.18 (d, 1H), 7.23 (d,1H), 7.31-7.35 (m, 3H), 7.78 (d, 2H); MS (ESI) m/z 508.3 (M).

EXAMPLE 13

[0105] Compound 36 (Scheme 3). Compound 36 was prepared as describedabove for the preparation of compound 10, this time employing carprofen(30) and 1,3-propanediol (3). After reaction, compound 36 was purifiedby column chromatography on a silica gel column using 200:1 CH₂Cl₂/MeOHas an eluent to give the compound 36 as a colorless oil with a 54%yield. ¹H NMR (CDCl₃) δ1.59 (d, 3H), 1.74 (br, 1H, D₂O ex), 1.80 (m,2H), 3.53-3.56 (m, 2H), 3.88 (q, 1H), 4.22-4.28 (m, 2H), 7.17 (d, 1H),7.29-7.35 (m, 3H), 7.94-7.98 (m, 2H), 8.14 (br, 1H); ¹³C NMR (CDCl₃)δ18.99, 31.84, 46.17, 59.42, 62.10, 109.70, 111.79, 119.79, 120.21,120.87, 121.92, 124.49, 125.22, 126.09, 138.24, 139.37, 140.55, 175.39;MS (ESI) m/z 332.2 (M+H).

[0106] Compound 42 (Scheme 3). Compound 42 was prepared as describedabove for the preparation of compound 18, this time employing compound36 and TsCl. Compound 42 was purified by column chromatography on asilica gel column using CH₂Cl₂ as an eluent to give the compound 42 as asticky oil and the yield was 90%; ¹H NMR (CDCl₃) δ1.55 (d, 3H), 1.91 (m,2H), 2.39 (s, 3H), 3.83 (q, 1H), 3.97 (t, 2H), 4.09-4.18 (m, 2H), 7.10(d, 1H), 7.21(d, 2H), 7.32 (s, 2H), 7.38 (s, 1H) 7.65 (d, 2H), 7.91 (d,1H), 7.98 (s, 1H), 8.54 (s, 1H); ¹³C NMR (CDCl₃) δ18.83, 21.77, 28.32,46.08, 60.59, 57.04, 109.97, 111.97, 119.58, 120.06, 120.69, 121.77,124.38, 125.00, 125.99, 127.95, 129.22, 130.06, 132.90, 138.38, 139.19,140.69, 145.15, 174.59; MS (ESI) m/z 486.3 (M+H).

EXAMPLE 14

[0107] Compound 37 (Scheme 3). Compound 37 was prepared as describedabove for the preparation of compound 10, this time employingindomethacin (31) and 1,3-propanediol (3). After reaction, compound 37was purified by column chromatography on a silica gel column using200:1; 100:1 CH₂Cl₂/MeOH as an eluents to give the compound 37 as a paleyellow oil with a 49% yield. ¹H NMR, ¹³C NMR and MS are consistent withthe structure of compound 37.

[0108] Compound 43 (Scheme 3). Compound 43 was prepared as describedabove for the preparation of compound 18, this time employing compound37 and TsCl. The compound 43 was purified by column chromatography on asilica gel column using hexane/ethyl acetate (3:1) as an eluent to givethe compound 43 as a pale yellow oil and the yield was 71% ; ¹H NMR(CDCl₃) δ1.97 (m, 2H), 2.36 (s, 3H), 2.44 (s, 3H), 3.63 (s, 2H), 3.83(s, 3H), 4.05 (t, 2H), 4.15 (t, 2H), 6.66-6.68 (m, 1H), 6.87 (d, 1H),6.93 (d, 1H), 7.33 (d, 2H), 7.47 (d, 2H), 7.67 (d, 2H), 7.75 (d, 2H); MS(ESI) m/z 592.0 (M+Na).

[0109] The syntheses described in Examples 15 and 16 are outlined inScheme 4.

EXAMPLE 15

[0110] Compound 46 (Scheme 4). Compound 46 was prepared as describedabove for the preparation of compound 18, this time employing compound11 and 44. The compound 46 was purified by crystallization fromether/hexane system to give the compound 46 as a white solid . The yieldwas 95%; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 2.00 (m, 2H), 2.73 (s, 3H), 3.87(q, 1H), 3.90 (s, 3H), 4.10 (t, 2H), 4.18 (t, 2H), 7.10-7.15 (m, 2H),7.39 (d, 1H), 7.66-7.71 (m, 3H); ¹³C NMR (CDCl₃) δ18.46, 28.55, 37.03,45.56, 55.47, 55.50, 60.38, 66.36, 105.75, 119.32, 126.09, 126.27,127.44, 129.06, 129.41, 133.89, 135.68, 157.91, 174.59; MS (ESI) m/z388.5 (M+Na).

EXAMPLE 16

[0111] Compound 47 (Scheme 4). Compound 47 is prepared as describedabove for the preparation of compound 18, this time employing compound11 and compound 45. The compound is purified by crystallization and theyield was 70-90%. The ¹H NMR, ¹³C NMR and MS are consistent with thestructure of compound 47.

[0112] The syntheses described in Examples 17 and 18 are outlined inScheme 5.

EXAMPLE 17

[0113] Compound 50 (Scheme 5). To a solution of naproxen (1) (1.15 g, 5mmol), compound 48 (0.62 g, 5 mmol) and dimethylamino pyridine (DMAP)(0.12 g, 1 mmol) was added dicyclohexyldicarbodiimide (DCC) (1.03 g, 5mmol) at 0° C. The resulting solution was stirred at 0° C. for 1.5 h.After reaction, the solid was filtered off and the solvent wasevaporated. The residue was washed with ether to give 1.4 g (83%) ofcompound 50 as a white solid; ¹H NMR (CDCl₃) δ1.59 (d, 3H), 2.38 (s,3H), 3.17 (m, 2H), 3.87 (q, 1H), 3.92 (s, 3H), 4.43 (m, 1H), 4.59 (m,1H), 7.10 (d, 1H), 7.15 (m, 1H), 7.33 (m, 1H), 7.67 (d, 1H), 7.70 (m,2H); MS (ES) m/e 358.2 (M+Na).

EXAMPLE 18

[0114] Compound 51 (Scheme 5). Compound 51 was prepared as describedabove for the preparation of compound 50, this time employing compound 1(1. 1 5 g, 5 mmol) and 49 (1.16 g, 5 mmol). The compound was purified bycolumn chromatography on a silica gel column using 1:1 hexanes/ethylacetate as eluent to give 0.91 g of compound 51 as a pale yellow oil; ¹HNMR (CDCl₃) δ1.45 (d, 3H), 3.48 (m, 2H), 3.59 (q, 1H), 3.92 (s, 3H),4.47 (m, 2H), 7.10 (d, 1H), 7.18 (m, 2H), 7.45 (s, 1H), 7.49 (t, 1H),7.65 (t, 2H), 8.06 (q, 1H), 8.28 (q, 1H), 8.68 (s, 1H); ¹³C NMR (CDCl₃)δ18.8, 45.2, 55.4, 55.5, 57.9, 105,8, 123.6, 125.9, 127.5, 128.4, 129.0,129.3, 130.8, 133.7, 133.9, 134.9, 141.5, 148.4, 158.0, 174.0.

[0115] The syntheses described in Examples 19-21 are outlined in Scheme6.

EXAMPLE 19

[0116] Compound 55 (Scheme 6). A mixture of compound 19 (2.2 g, 5 mmol),compound 52 (0.57 g, 6 mmol) and K₂CO₃ (3.45 g, 25 mmol) in 50 ml ofdimethyl formamide (DMF) was stirred for a week. The reaction solutionwas poured into 100 ml of water and extracted with CH₂Cl₂. The organicphase was washed with water (50×5) and dried (Na₂SO₄). The solvent wasevaporated and the residue was purified by column chromatography on asilica gel column using 3:1 hexane/ethyacetate as an eluent to give 0.3g (16%) of compound 55 as a pale yellow oil; ¹H NMR (CDCl₃) δ1.60 (d,3H), 2.38 (s, 3H), 3.17 (m, 2H), 3.87 (q, 1H), 3.92 (s, 3H), 4.45 (m,1H), 4.59 (m, 1H), 7.10 (s, 1H), 7.14-7.16 (q, 1H), 7.32-7.35 (q, 1H),7.62 (s, 1H), 7.67-7.71 (m, 2H); MS (ESI) m/z 358.2 (M+Na).

EXAMPLE 20

[0117] Compound 56 (Scheme 6). Compound 56 was prepared as describedabove for the preparation of compound 55, this time employing compound19 and compound 53. The compound was purified by column chromatographyon a silica gel column using CH₂Cl₂ as an eluent to give compound 56 asa pale yellow oil (33%). ¹H NMR (CDCl₃) δ1.54 (d, 3H), 1.72 (m, 2H),2.83 (m, 2H), 3.80 (q, 1H), 3.92 (s, 3H), 4.10 (t, 2H) 7.07-8,10 (m,10H); MS (ESI) m/z 442.3 (M+H).

EXAMPLE 21

[0118] Compound 57 (Scheme 6). Compound 57 was prepared as describedabove for the preparation of compound 55, this time employing compound19 and compound 54. The compound was purified by column chromatographyon a silica gel column using CH₂Cl₂ as an eluent to give compound 57 asa pale yellow oil (11%). ¹H NMR (CDCl₃) δ1.55 (d, 3H), 1.80 (m, 2H),3.03 (m 2H),3.86 (m, 1H), 4.13 (m, 2H), 7.07-7.93 (m, 10H); MS (ESI) m/z473.4 (M+H).

[0119] The syntheses described in Examples 22 and 23 are outlined inScheme 7.

EXAMPLE 22

[0120] Compound 60 (Scheme 7). Compound 60 is prepared as describedabove for the preparation of compound 50, this time employing naproxen(1) and compound 58. After reaction the compound is purified by columnchromatography on a silica gel column to give the compound 60 in a yieldfrom 75-95%.

EXAMPLE 23

[0121] Compound 61 (Scheme 7). Compound 61 is prepared as describedabove for the preparation of compound 50, this time employing naproxen(1)and compound 59. After reaction, the compound is purified by columnchromatography on a silica gel column to give compound 61 in a yieldfrom 75-95%.

[0122] The syntheses described in Examples 24 and 25 are outlined inScheme 8.

EXAMPLE 24

[0123] Compound 63 (Scheme 8). Compound 63 is prepared as describedabove for the preparation of compound 50, this time employing naproxen(1) and compound 62. After reaction, the compound is purified by columnchromatography on a silica gel column to give compound 63 in a yield of75-95%.

[0124] Compound 66 (Scheme 8). Compound 66 is prepared as describedabove for the preparation of compound 18, this time employing compound63 and compound 64.

EXAMPLE 25

[0125] Compound 67 (Scheme 8). Compound 67 is prepared as describedabove for the preparation of compound 18, this time employing compound63 and compound 65.

[0126] The syntheses described in Examples 26 and 27 are outlined inScheme 9.

EXAMPLE 26

[0127] Compound 70 (Scheme 9). Compound 70 is prepared as describedabove for the preparation of compound 60, this time employing compound 1and compound 68.

EXAMPLE 27

[0128] Compound 71 (Scheme 9). Compound 71 is prepared as describedabove for the preparation of compound 60, this time employing compound 1and compound 69.

[0129] The synthesis described in Example 28 is outlined in Scheme 10.

EXAMPLE 28

[0130] Compound 73 (Scheme 10). Compound 73 is prepared as describedabove for the preparation of compound 60, this time employing compound 1and compound 72.

[0131] The synthesis described in Example 29 is outlined in Scheme 11.

EXAMPLE 29

[0132] Compound 75 (Scheme 11). To a solution of naproxen 1 (1.15 g, 5.0mmol) and 1,3-dicyclohexylcarbodiimide (DCC)(1.03 g, 5 mmol) in 180 mlof anhydrous tedrahydrofuran (THF) was added4-(2-aminoethyl)benzenesulfonamide 74 (1.1 g, 5.5 mmol) at rt. Theresulting mixture was stirred overnight. The resulted solid was filteredoff and the solvent was evaporated. The residue was partially dissolvedin ethyl acetate and filtered to remove more solid. The filtrate wasevaporated and the residue was purified by flash chromatography on asilica gel column using CH₂Cl₂ and 100:1 CH₂Cl₂-MeOH as eluents to give0.1 g (5%) of the compound 75 as a white solid; ¹H NMR (DMSO-d₆) δ1.38(d, 3H), 2.73 (m, 3H, 1H, ex D₂O), 3.68 (q, 1H), 3.86 (s, 3H), 7.13-8.08(m, 12H, 2H, ex D₂O); MS (ESI) m/z 413.1 (M+H)⁺ (C₂₂H₂₅N₂O₄S require413.5).

[0133] The syntheses described in Examples 30 and 31 are outlined inScheme 12.

EXAMPLE 30

[0134] Compound 78 (Scheme 12). To a solution of naproxen 1 (1.15 g, 5mmol) and benzenesulfonyl hydrazide 76 (0.86 g, 5 mmol) in 50 ml ofCH₂Cl₂ was added DCC (1.03 g, 5 mmol) at rt. The resulting solution wasstirred at rt for 26 h. The resulted solid was filtered off and thefiltrate was washed with 5% Na₂CO₃ solution, 0.5N HCl solution andwater. The organic phase was dried with anhydrous sodium sulfate(Na₂SO₄) and concentrated. The residue was purified by flashchromatography on a silica gel column using 5:1 and 2:1 hexanes-EtOAc aseluents to give 1.44 g (75%) of the compound 78 as a white solid; ¹H NMR(CDCl₃) δ1.37 (d, 3H), 3.54 (q, 1H), 3.94 (s, 3H), 7.12-7.77 (m, 13H,2H, ex D₂O); MS (ESI) m/z 385.0 (M+H)⁺ (C₂₀H₂₁N₂O₄S requires 385.1).

EXAMPLE 31

[0135] Compound 79 (Scheme 12). Compound 79 was prepared by the similarprocedure as described above for compound 78 from4-methoxybenzenesulfonyl hydrazide 77 (1.01 g, 5 mmol), naproxen 1 (1.15g, 5 mmol) and DCC (1.03 g, 5 mmol). The compound was purified by flashchromatography on a silica gel column using 200:1 CH₂Cl₂-MeOH as aneluent to give 0.69 g (33%) of the compound 79 as a white solid; ¹H NMR(CDCl₃) δ1.38 (d, 3H), 3.57 (q, 1H), 3.68 (s, 3H), 3.92 (s, 3H),6.60-8.13 (12H, 2H ex D₂O); MS (ESI) m/z 415.7 (M+H)⁺ (C₂₁H₂₃N₂O₅Srequires 415.2).

[0136] The syntheses described in Examples 32-35 are outlined in Scheme13.

EXAMPLE 32

[0137] Compound 84 (Scheme 13). To a solution of naproxen 1 (1.15 g, 5mmol) and 2-(methylthio)ethanol 80 (0.46 g, 5 mmol) and4-(dimethylamino)pyridine (DMAP) (0.12 g, 1 mmol) in 50 ml of CH₂Cl₂ wasadded DCC (1.03 g, 5 mmol) at 0° C. The resulting solution was stirredat 0° C. for 2 h. The solid was filtered off and the solvent wasevaporated. The residue was partially dissolved in EtOAc and the mixturewas filtered to remove more solid. The filtrate was washed with water(50×2), dried (Na₂SO₄) and concentrated. Recrystallization of the crudeproduct from hexanes provided 0.96 g of the compound 84 as a whitecrystal; ¹H NMR (CDCl₃) δ1.59 (d, 3H), 2.05 (s, 3H), 2.65 (m. 2H), 3.86(q, 1H), 3.91 (s, 3H), 4.25 (m, 2H), 7.11-7.25 (m, 2H), 7.41 (d, 1H),7.67-7.71 (m, 3H); ¹³C NMR (CDCl₃) δ15.9, 16.8, 32.6, 45.6, 55.5, 63.7,105.8, 119.2, 126.2, 126.4, 127.4, 129.1, 129.4, 133.9, 135.7, 157.9,174.7; MS (ESI) m/z 327.4 (M+Na)⁺ (Cl₇H₂₀O₃SNa requires 327.1).

[0138] Compound 50 (Scheme 13). To a solution of compound 84 (0.09 g,0.3 mmol) in 3 ml of acetone was added m-chloroperoxybenzoic acid(m-CPBA) (0.25 g, 1.5 mmol). The resulting solution was stirred at 0° C.for 3 h. A solution of Na₂SO₃ was added to quench the reaction and thenmore water was added. The resulted mixture was filtered and washed withmethanol to give a compound which has the identical ¹H NMR and MSproperties to compound 50 produced by the procedure set forth in Example17 above.

EXAMPLE 33

[0139] Compound 85 (Scheme 13). Compound 85 was prepared by the similarprocedure as described above for compound 84 from naproxen 1 (6.9 g, 30mmol), methylthiopropanol 81 (3.06 ml, 3.18 g, 30 mmol), DMAP (0.72 g, 6mmol) and DCC (6.18 g, 30 mmol). The compound was purified byrecrystallization from hexanes to give 6.7 g (70%) of the compound 85 asa white crystal; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 1.85 (m, 2H), 1.97 (s,3H), 2.39 (t, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.17 (m, 2H), 7.11-7.15(m, 2H), 7.39-7.41 (m, 1H), 7.66-7.71 (m, 3H); MS (ESI) m/z 441.5(M+Na)⁺. (C₁₈H₂₂O₃SNa requires 441.2).

[0140] Compound 88 (Scheme 13). Compound 88 was prepared by the similarprocedure as described above for compound 50 from compound 85 (1.27 g, 4mmol) and m-CPBA (3.4 g, 20 mmol). The product was purified byrecrystallization from EtOAc-hexanes to give 1.1 g (80%) of the compound88 as a white powder; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 2.08 (m, 2H), 2.59(s, 3H), 2.75 (m, 2H), 3.86 (q, 1H), 3.91 (s, 3H), 4.16 (m, 1H), 4.26(m, 1H), 7.11-7.16 (m, 2H), 7.37-7.39 (m, 1H), 7.66 (s, 1H), 7.70-7.73(m, 2H); MS (ESI) m/z 373.3 (M+Na)⁺ (C₁₈H₂₂O₃SNa requires 373.1).

EXAMPLE 34

[0141] Compound 86 (Scheme 13). Compound 86 was prepared by the similarprocedure as described above for compound 84 from naproxen 1 (6.9 g, 30mmol), methylthiobutanol 82 (3.6 g, 30 mmol), DCC (6.18 g, 30 mmol) andDMAP (0.72 g, 6 mmol). The product was purified by recrystallizationfrom hexanes to give 7.3 g (73%) of the compound 86 as a white solid; ¹HNMR (CDCl₃) δ1.54 (m, 2H), 1.58 (d, 3H), 1.67 (m, 2H), 1.96 (s, 3H),2.40 (t, 2H), 3.85 (q, 1H), 3.89 (s, 3H), 4.09 (t, 2H), 7.10-7.15 (m,2H), 7.39-7.41 (q, 1H), 7.66-7.70 (t, 3H); ³C NMR (CDCl₁₃) δ15.35,18.59, 25.48, 27.74, 33.72, 45,61, 55.3, 64.37, 105.70, 119.08, 126.02,126.32, 127.24, 129.04, 129.37, 133.80, 135.85, 157.74, 174.76; MS (ESI)m/z 355.3 (M+Na)⁺ (C₁₉H₂₄O₃SNa requires 355.1).

[0142] Compound 89 (Scheme 13). Compound 89 was prepared by the similarprocedure as described above for compound 50 from compound 86 (1.33 g, 4mmol), m-CPBA (3.5 g, 20 mmol) in 35 ml of acetone. The product waspurified by recrystallization from CH₂Cl₂-hexane to give 1.13 g (78%) ofthe compound 89 as a pale yellow solid; ¹H NMR (CDCl₃) δ1.57 (d, 3H),1.73 (m, 4H), 2.56 (s, 3H), 2.82 (m, 2H), 3.65 (q, 1H), 3.90 (s, 3H),4.08 (m, 1H), 4.15 (m, 1H), 7.10-7.15 (m, 2H), 7.38-7.40 (q, 1H), 7.65(s, 1H), 7.70 (d, 2H); ¹³C NMR (CDCl₃) δ18.5, 19.4, 27.5, 40.2, 45.6,54.2, 55.5, 63.7, 105.8, 119.4, 126.1, 126.3, 127.4, 129.1, 129.4,133.9, 135.8, 157.9, 174.7; MS (ESI) m/z 387.5 (M+Na)⁺ (C₁₉H₂₄O₅SNarequires 387.5).

EXAMPLE 35

[0143] Compound 87 (Scheme 13). Compound 87 was prepared by the similarprocedure as described above for compound 84 from naproxen 1 (1.15 g, 5mmol), 2-(phenylthio)ethanol 83 (0.77 g, 5 mmol), DCC (1.03 g, 5 mmol)and DMAP (0.12 g, 1 mmol) in 50 ml of CH₂Cl₂. The product was purifiedby recrystallization from hexanes to give 1.0 g (56%) of the compound 87as a white powder; ¹H NMR (CDCl₃) δ1.56 (d, 3H), 3.10 (m, 2H), 3.83 (q,1H), 3.91 (s, 3H), 4.25 (m, 2H), 7.11-7.40 (m, 8H), 7.65-7.70 (m, 3H);¹³C NMR (CDCl₃) δ18.7, 32.5, 45.6, 55.5, 63.4, 105.8, 119.2, 126.2,126.4, 126.8, 127.4, 129.1, 129.2, 129.5, 130.1, 133.9, 135.3, 135.7,157.9, 174.7; MS (ESI) m/z 389.5 (M+Na)⁺ (C₂₂H₂₂O₂SNa requires 389.2).

[0144] Compound 90 (Scheme 13). Compound 90 was prepared by the similarprocedure as described above for compound 50 from compound 87 (1.46 g, 4mmol), m-CPBA (3.5 g, 20 mmol) in 35 ml of acetone. The product waspurified by recrystallization from CH₂Cl₂-hexane to give 1.2 g (75%) ofthe compound 90 as a white solid; ¹H NMR (CDCl₃) δ1.46 (d, 3H), 3.40 (m,2H), 3.59 (q, 1H), 3.92 (s, 3H), 4.33 (m, 1H), 4.45 (m, 1H), 7.11-7.85(m, 11H); ¹³C NMR (CDCl₃) δ18.6, 45.2, 55.2, 55.5, 58.1, 105.8, 119.3,126.2, 127.4, 128.3, 129.1, 129.4. 129.5, 133.9, 134.1, 135.1, 139.5,158.0, 174.2; MS (ESI) m/z 399.4 (M+H)⁺ (C₂₂H₂₃O₅S requires 399.5).

[0145] The synthesis described in Example 36 is outlined in Scheme 14.

EXAMPLE 36

[0146] Compound 92 (Scheme 14). Compound 92 was prepared by the similarprocedure as described above for compound 84 from methylthiobenzenealcohol 91 (4.6 g, 30 mmol), naproxen 1 (6.9 g, 30 mmol), DCC (6.18 g,30 mmol) and DMAP (0.72 g, 6 mmol). The product was purified byrecrystallization from CH₂Cl₂-hexanes to give 8.6 g (78%) of thecompound 92 as a white crystal; ¹H NMR (CDCl₃) δ1.58 (d, 3H), 2.45 (s,3H), 3.89 (q, 1H), 3.92 (s, 3H), 5.05 (q, 2H), 7.11-7.16 (m, 6H),7.37-7.39 (m, 1H),7.63-7.70 (m, 3H); ¹³C NMR (CDCl₃) δ15.9, 18.7, 45.7,55.5, 66.3, 105.8, 119.2, 126.2, 126.5, 126.7, 127.3, 128.9, 129.1,129.5, 132.9, 133.9, 135.7, 138.8, 157.9, 174.6; MS (ESI) m/z 389.4(M+Na)⁺ (C₂₂H₂₂O₃Sna requires 389.5)

[0147] Compound 93 (Scheme 14). Compound 93 was prepared by the similarprocedure as described above for compound 50 from compound 92 (1.1 g, 3mmol), m-CPBA (1.34 g, 7.5 mmol) in 30 ml of acetone. The product waspurified by flash chromatography on a silica gel column using CH₂Cl₂ asan eluent to give 1.0 g (85%) of the compound 93 as a white solid; ¹HNMR(CDCl₃) δ1.61 (d, 3H), 2.99 (s, 3H), 3.92 (s, 3H), 3.93 (q, 1H), 5.18(q, 2H), 7.12-7.16 (m, 2H), 7.34-7.39 (m, 3H), 7.66-7.71 (m, 3H), 7.81(d, 2H); ¹³C NMR (CDCl₃) δ18.5, 44.7, 45.6, 55.5, 65.3, 105.8, 119.4,126.2, 126.3, 127.5, 127.8, 128.3, 129.1, 129.4, 133.9, 135.3, 140.2,142.5, 158.0, 174.4; MS (ESI) m/z 398.9 M⁺ (C₂₂H₂₂O₅S requires 398.5)

[0148] The synthesis described in Example 37 is outlined in Scheme 15.

EXAMPLE 37

[0149] Compound 95 (Scheme 15). A mixture of 2,2′-sulfonyldiethanol 94(12.5 ml, 60% in H₂O, 9.25 g, 60 mmol) and CHCl₃ was heated to reflux toremove the water and then naproxen 1 (4.6 g, 20 mmol) and4-toluenesulfonic acid (TsOH) (0.25 g, 1.3 mmol) were added to the abovemixture. The resulting mixture was continued to reflux for 6 h. Thereaction mixture was washed with water twice, 10% Na₂CO₃ solution twiceand then water once. The organic phase was dried (Na₂SO₄) and thesolvent was evaporated. The crude product was recrystallized fromCHCl₃-hexanes to give 0.41 g of the compound 95 as a white powder; ¹HNMR (CDCl₃) δ1.60 (d, 3H), 1.85 (bs, 1H, ex D₂O), 2.51-2.56 (m, 1H),2.62-2.67 (m, 1H), 3.25-3.28 (m, 2H), 3.48-3.51 (m, 2H), 3.88 (q, 1H),3.92 (s, 3H), 4.41-4.46 (m, 1H), 4.56-4.61 (m, 1H), 7.11 (d, 1H),7.15-7.18 (q, 1H), 7.35-7.36 (q, 1H), 7.65 (s, 1H), 7.69-7.74 (m, 2H);¹³C NMR (CDCl₃) δ18.3, 45.6, 54.0, 55.5, 55.6, 56.2, 56.3, 58.6, 105.8,119.8, 126.1, 126.4, 127.7, 129.0, 133.9, 135.2, 158.2, 173.9; MS (ESI)m/z 389.1 (M+Na)⁺ (C₁₈H₂₂O₆Sna requires 389.1).

[0150] The syntheses described in Examples 38-45 are outlined in Scheme16.

EXAMPLE 38

[0151] Compound 102 (Scheme 16). A solution of compound 12 (3.02 g, 10mmol) and methansulfonyl chloride 96 (1.55 ml, 2.29 g, 20 mmol) in 10 mlof pyridine was stirred at 0° C. for 2 h. 100 ml of water was added andthe resulting mixture was filtered and the solid was washed with waterfive times. The compound was purified by rerecrystallization fromCH₂Cl₂-hexanes to give 3.0 g (79%) of the compound 102 as a white solid;¹H NMR (CDCl₃) δ1.58 (d, 3H), 1.67 (m, 4H), 2.88 (s, 3H), 3.85 (q, 1H),3.91 (s, 3H), 4.10 (m, 4H), 7.11-7.15 (m, 2H), 7.38-7.40 (q, 1H),7.65-7.71 (s, 3H); ¹³C NMR (CDCl₃) δ18.6, 24.9, 25.9, 37.5, 45.6, 55.5,63.9, 69.4, 105.8, 119.2, 126.1, 126.4, 127.4, 129.1, 129.4, 133.9,136.8, 157.9, 174.8; MS (ESI) m/z 403.6 (M+Na)⁺ (C₁₉H₂₄O₆Sna requires403.5).

EXAMPLE 39

[0152] Compound 103 (Scheme 16). Compound 103 was prepared by thesimilar procedure as described above for compound 102 from compound 13(4.74 g, 15 mmol) and compound 96 (2.31 ml, 3.43 g, 30 mmol). Theproduct was purified by recrystallization from CH₂Cl₂-hexanes to give5.1 g (86%) of the compound 103 as a white solid; ¹H NMR (CDCl₃) δ1.30(m, 2H), 1.58 (d, 3H), 1.62(m, 4H), 2.9 (s, 3H), 3.89 (q, 1H), 3.91 (s,3H), 4.02-4.11 (m, 4H), 7.11-7.15 (m, 2H), 7.39 (d, 1H), 7.66-7.71 (m,3H); ¹³C NMR (CDCl₃) δ18.5, 22.1, 28.1, 28.8, 37.4, 45.7, 55.5, 64.5,69.8, 105.8, 119.2, 126.1, 126.4, 127.3, 129.4, 133.9, 135.9, 157.9,174.9; MS (ESI) m/z 395.1 (M+H)⁺ (C₂₀H₂₇O₆S requires 395.1).

EXAMPLE 40

[0153] Compound 104 (Scheme 16). Compound 104 was prepared by thesimilar procedure as described above for compound 102 from compound 14(3.3 g, 10 mmol) and compound 96 (1.55 ml, 2.31 g, 20 mmol). The productwas purified by recrystallization from CH₂Cl₂-hexanes to give 1.72 g(42%) of the compound 104 as a white solid; ¹H NMR (CDCl₃) δ1.21-1.31(m, 4H), 1.53-1.61 (m, 7H), 2.95 (s, 3H), 3.89 (q, 1H), 3.91 (s, 3H),4.04-4.12 (m, 4H), 7.12-7.15 (m, 2H), 7.40 (q, 1H), 7.69 (t, 3H); MS(ESI) m/z 431.4 (M+Na)⁺ (C₂₁H₂₈O₆Sna requires 431.5).

EXAMPLE 41

[0154] Compound 105 (Scheme 16). Compound 105 was prepared by thesimilar procedure as described above for compound 103 from compound 12(1.5 1 g, 5 mmol) and compound 100 (0.94 ml, 1.28 g, 10 mmol). Theproduct was purified by flash chromatography on a silica gel columnusing CH₂Cl₂ as an eluent to give 1.45 g (74%) of the compound 105 as apale yellow oil; ¹H NMR (CDCl₃) δ1.35 (t, 3H), 1.57(d, 3H), 1.68 (m,4H), 3.01(q, 2H), 3.84 (q, 1H), 3,90 (s, 3H), 4.11 (m, 4H); MS (ESI) m/z417.4 (M+Na)⁺ (C₂₀H₂₆O₆Sna requires 417.5).

EXAMPLE 42

[0155] Compound 106 (Scheme 16). Compound 106 was prepared by thesimilar procedure as described above for compound 102 from compound 12(1.51 g, 5 mmol) and compound 97 (1.27 ml, 1.76 g, 10 mmol). The productwas washed with water and dried to give 1.9 g (86%) of the compound 106as a pale yellow oil; ¹H NMR (CDCl₃) δ1.53 (d, 3H), 1.55-1.63 (m, 4H),3.81 (q, 1H), 3.91 (s, 3H), 3.94-4.03 (m, 4H), 7.11-7.15 (m, 2H), 7.36(d, 1H), 7.51(m, 2H), 7.63 (m, 2H), 7.69 (d, 2H), 7.85 (d, 2H); MS (ESI)m/z 443.6 (M+H)⁺ (C₂₄H₂₇O₆S requires 443.5).

EXAMPLE 43

[0156] Compound 107 (Scheme 16). Compound 107 was prepared by thesimilar procedure as described above for compound 102 from compound 12(1.51 g, 5 mmol) and compound 98 (1.55 ml, 2.45 g, 10 mmol). The productwas purified by flash chromatography on a silica gel column using CH₂Cl₂as an eluent to give 1.12 g (44%) of the compound 107 as a white solid;¹H NMR (CDCl₃) δ1.56 (d, 3H), 1.60-1.63 (m, 4H), 3.82 (q, 1H), 3.90 (s,3H), 4.00-4.06 (m, 4H), 7.11-7.15 (m, 2H), 7.36-7.38 (q, 1H), 7.64-7.71(m, 4H), 7.89 (d, 1H), 8.04 (d, 1H), 8.15 (s, 1H); ¹³C NMR (CDCl₃)δ18.5, 24.8, 25.7, 45.6, 55.5, 63.7, 70.8, 105.8, 119.2, 125.06, 125.09,126.3, 127.4, 129.1, 129.4, 130.3, 130.6, 131.2, 132.1, 133.9, 135.8,137.6, 157.9, 174.8; MS (ESI) m/z 533.3 (M+Na)⁺ (C₂₅H₂₅F₃O₆Sna requires533.5).

EXAMPLE 44

[0157] Compound 108 (Scheme 16). Compound 108 was prepared by thesimilar procedure as described above for compound 102 from compound 12(1.51 g, 5 mmol) and compound 99 (2.06 g, 10 mmol). The product waspurified by recrystallization from CH₂Cl-₂-hexanes to give 1.44 g (61%)of compound 108 as a white crystal; 1H NMR and MS spectra areconsistence with the compound 108.

EXAMPLE 45

[0158] Compound 109 (Scheme 16). Compound 109 was prepared by thesimilar procedure as described above for compound 102 from compound 13(1.58 g, 5 mmol) and compound 101 (2.21 g, 10 mmol). The product waspurified by flash chromatography on a silica gel column using CH₂Cl₂ asan eluent to give 1.5 g (67%) of the compound 109 as a pale yellow oil;¹H NMR (CDCl₃) δ1.21-1.26 (m, 2H), 1.50-1.59 (m, 7H), 3.83 (q, 1H), 3.91(s, 3H), 3.89-4.08 (m, 4H), 7.11-7.26 (m, 2H), 7.37-7.40 (m, 1H),7.63-7.70 (m, 3H), 8.02 (d, 2H), 8.35 (d, 2H); MS (ESI) m/z 524.6(M+Na)⁺ (C₂₅H₂₇NO₈Sna requires 524.6).

[0159] The syntheses described in Examples 46 and 47 are outlined inScheme 17.

EXAMPLE 46

[0160] Compound 111 (Scheme 17). A mixture of compound 20 (4.56 g, 10mmol), methanesulfonamide 110 (1.9 g, 20 mmol, 2 equiv) and K₂CO₃ (6.9g, 50 mmol, 5 equiv) in 100 ml of acetonitril (CH₃CN) was heated toreflux for 26 h. The solvent was evaporated and the residue wasdissolved and shaken well in water and EtOAc. The two phases wereseparated and the organic phase was washed with water three times, dried(Na₂SO₄) and concentrated. The crude product was purified byrecrystallization from CH₂Cl₂-hexanes to give 2.53 g (67%) of thecompound 111 as an yellow solid; ¹H NMR (CDCl₃) δ1.38-1.42 (m, 2H),1.53-1.63 (m, 2H), 1.58 (d, 3H), 2.77 (s, 3H), 2.92-2.96 (m, 2H), 3.85(q, 1H), 3.91 (s, 3H), 3.99 (bs, 1H, ex D₂O), 4.03-4.07 (m, 1H),4.11-416 (m, 1H), 7.12-7.16 (m, 2H), 7.38-7.40 (d, 1H), 7.66 (s, 1H),7.71 (d, 2H); MS (ESI) m/z 402.5 (M+Na)⁺ (C₁₉H₂₅NO₅SNa requires 402.5).

EXAMPLE 47

[0161] Compound 112 (Scheme 17). Compound 112 was prepared by thesimilar procedure as described above for compound 111 from compound 22(2.42 g, 5 mmol) and compound 110 (0.57 g, 6 mmol, 1.2 equiv). Theproduct was purified by recrystallization from CH₂Cl₂-hexanes to give0.9 g (45%) of the compound 112 as a powder; ¹H NMR (CDCl₃) δ1.17-1.22(m, 4H), 1.33-1.37 (m, 2H), 1.56 (d, 3H), 1.52-1.60 (m, 2H), 2.89 (s,3H), 2.95 (q, 2H), 3.85 (q, 1H), 3.91 (s, 3H), 4.01-4.15 (m, 3H, 1H exD₂O), 7.12-7.15 (m, 2H), 7.40 (d, 1H), 7.66-7.76 (m, 3H); ¹³C NMR(CDCl₃) δ18.5, 25.5, 26.1, 28.5, 30.1, 40.5, 43.2, 45.7, 55.5, 64.6,105.8, 119.2, 126.1, 126.5, 127.3, 129.1, 129.4, 133.9, 136.1, 157.8,174.9; MS (ESI) m/z 430.6 (M+Na)⁺ (C₂₁H₂₉NO₅Sna requires 430.6).

[0162] The syntheses described in Examples 48 and 49 are outlined inScheme 18.

EXAMPLE 48

[0163] Compound 116 (Scheme 18). To a solution of aminopentanol 113 (3.1g, 30 mmol) and triethylamine (TEA) (4.2 ml, 3.03 g, 30 mmol) in 50 mlof anhydrous THF was added dropwise p-toluenesulfonyl chloride 115 (5.7g, 30 mmol) in 50 ml of THF at 0° C. The resulting solution wascontinued to stirr at 0° C. and then rt for 2 h. To the reactionsolution was added 500 ml of water and the resulted mixture wasextracted with EtOAc. The combined organic phase was washed with watertwice, 0.5 N HCl solution once, 5% NaHCO₃ solution once and water once.The organic phase was dried (Na₂SO₄) and evaporated under high vacuum togive 4.87 g (63%) of the compound 116 as a white oil. The compound wasused to prepare compound 118 without further purification; ¹H NMR(CDCl₃) δ1.33-1.37 (m, 2H), 1.45-1.51 (m, 4H), 2.41 (s, 3H), 2.91 (t,2H), 3.57 (t, 2H), 7.30 (d, 2H), 7.72 (d, 2H); MS (ESI) m/z 280.5(M+Na)⁺ (C₁₂H₁₉NO₃SNa requires 280.4).

[0164] Compound 118 (Scheme 18). To a solution of compound 116 (1.29 g,5 mmol), naproxen 1 (1.15 g, 5 mmol) and DMAP (0.12 g, 1 mmol) in CH₂Cl₂was added DCC (1.03 g, 5 mmol) at 0° C. The resulting solution wasstirred at 0° C. for 2 h and then at rt for another 2 h. The solid wasfiltered off and the solvent was evaporated. The residue was dissolvedin EtOAc and filtered to remove more solid. The filtrate was washed withwater three times, dried (Na₂SO₄) and concentrated. The product waspurified by flash chromatography on a silica gel column using ethylether as an eluent to give 2.06 g (88%) of the compound 118 as a solid;¹H NMR (CDCl₃) δ1.13-1.18 (m, 2H), 1.25-1.34 (m, 2H), 1.45-1.51 (m, 2H),1.55 (d, 3H), 2.40 (s, 3H), 2.77 (q, 2H), 3.81 (q, 1H), 3.90 (s, 3H),3.96-4.02 (m, 2H), 4.47 (t, 1H, ex D₂O), 7.12-7.14 (m, 2H), 7.26 (d,2H), 7.38 (d, 1H), 7.65-7.70 (m, 5H); MS (ESI) m/z 492.5 (M+Na)⁺(C₂₆H₃₁NO₅SNa requires 492.6).

EXAMPLE 49

[0165] Compound 117 (Scheme 18). Compound 117 was prepared by thesimilar procedure as described above for compound 116 from6-amino-1-hexanol 114 (3.5 g, 30 mmol) and compound 115 (5.7 g, 30mmol). The product was purified by flash chromatography on a silica gelcolumn using ethyl ether as an eluent to give 6.5 g (80%) of thecompound 117 as a white solid; ¹H NMR (CDCl₃) δ1.26-1.29 (m, 4H),1.43-1.49 (m, 4H), 2.40 (s, 3H), 2.89 (t, 2H), 3.57 (t, 2H), 7.27 (d,2H), 7.73 (d, 2H); MS (ESI) m/z 272.4 (M+H)⁺ (C₁₃H₂₂NO₃S requires272.4).

[0166] Compound 119 (Scheme 18). Compound 119 was prepared by thesimilar procedure as descibed above for compound 118 from compound 117(1.36 g, 5 mmol), naproxen 1 (1.15 g, 5 mmol), DCC (1.03 g, 5 mmol) andDMAP (0.12 g, 1 mmol). The product was purified by flash chromatographyon a silica gel column using ethyl ether as an eluent to give 2.04 g(84%) of the compound 119 as a white solid; ¹H NMR (CDCl₃) δ1.11 (m,4H), 1.23-1.29 (m, 2H), 1.46-1.56 (m, 2H), 1.56 (d, 3H), 2.40 (s, 3H),2.79 (q, 2H), 3.82 (q, 1H), 3.91 (s, 3H), 3.96-4.05 (m, 2H), 4.43 (t,1H, ex D₂O ), 7.11-7.14 (m, 2H), 7.26-7.29 (m, 2H), 7.37-7.39 (q, 1H),7.64-7.72 (m, 5H); ¹³C NMR (CDCl₃) δ18.5, 21.7, 25.4, 26.1, 28.4, 29.5,43.1, 45.7, 55.5, 64.6, 105.8, 119.1, 126.1, 126.4, 127.3, 129.1, 129.4,129.8, 133.8, 136.1, 137.2, 143.5, 157.8, 174.1; MS (ESI) m/z 484.7(M+H)⁺ (C₂₇H₃₄NO₅S requires 484.6).

[0167] The syntheses described in Examples 50 and 51 are outlined inScheme 19.

EXAMPLE 50

[0168] Compound 123 (Scheme 19). A mixture of naproxen sodium 120 (2.52g, 10 mmol) and propanesulton 121 (1.22 g, 10 mmol) in 50 ml ofN,N-dimethylformamide (DMF) was stirred at 50-60° C. for 30 min. To thereaction solution was added 150 ml of acetone and then stood still for 1h. Filtration and washing by acetone provided 3.2 g (86%) of thecompound 123 as a white powder; ¹HNMR (D₂O ) δ1.37 (d, 3H), 1.93-1.97(m, 2H), 2.74-2.77 (m, 2H), 3.72 (q, 1H), 3.72 (s, 3H), 4.01-4.05 (m,1H), 4.08-4.11 (m, 1H), 6.97-7.00 (m, 2H), 7.20-7.22 (q, 1H), 7.44 (s,1H), 7.50 (t, 2H); ¹³C NMR (D²O) δ16.7, 23.1, 44.4., 46.9, 54.6, 63.2,105.4, 117.9, 125.1, 125.5, 126.7, 128.1, 128.7, 132.7, 134.9, 156.3,176.4; MS (ESI) m/z 397.1 (M+Na)⁺ (C₁₇H₁₉Na₂O₅S requires 397.4).

EXAMPLE 51

[0169] Compound 124 (Scheme 19). Compound 124 was prepared by thesimilar procedure as described above for compound 123 from butanesulton122 (1.02 ml, 1.36 g, 10 mmol) and naproxen sodium 120 (2.52 g, 10mmol). After reaction, acetone was added and the solid was filtered andwashed with acetone to give 1.3 g (34%) of the compound 124 as a whitepowder; ¹HNMR (D₂O ) δ1.22 (d, 3H), 1.34-1.38 (m, 2H), 1.50-1.56 (m,2H), 2.65 (t, 2H), 3.44 (s, 3H), 3.47 (m, 1H), 3.74-3.77 (m, 1H),3.83-3.86 (m, 1H), 6.74 (s, 1H), 6.78-6.81 (d, 1H), 7.05 (d, 1H),7.22-7.29 (m, 3H); MS (ESI) m/z 411.2 (M+Na)⁺ (C₁₈H₂₁Na₂O₆S requires411.2).

[0170] The synthesis described in Example 52 is outlined in Scheme 20.

EXAMPLE 52

[0171] Compound 125 (Scheme 20). To a mixture of diclofenac 29 (2.96 g,10 mmol), methylsulfonylethanol 48 (1.24 g, 10 mmol) and DMAP (0.24 g, 2mmol) in 50 ml of CH₂Cl₂ was added DCC (2.06 g, 10 mmol) at 0° C. Theresulting mixture was stirred at 0° C. for 2 h. The mixture was filteredand the filtrate was evaporated. The residue was washed with methanol togive 1.83 g (92%) of the compound 125 as a white powder; ¹H NMR (CDCl₃)2.75 (s, 3H), 3.30 (t, 2H), 3.84 (s, 2H), 4.58 (t, 2H), 6.51 (d, 1H),6.93 (t, 1H), 7.00 (t, 1H), 7.12 (t, 1H), 7.19 (d, 1H), 7.34 (d, 2H);¹³C NMR (CDCl₃) δ38.5, 42.1, 54.0, 58.8, 118.3, 122.2, 123.4, 124.7,128.6, 129.1, 129.9, 131.1, 137.6, 142.8, 171.5; MS (ESI) m/z 402.4 M⁺(C₁₇H₁₇Cl₂NO₄S requires 402.4).

[0172] The synthesis described in Example 53 is outlined in Scheme 21.

EXAMPLE 53

[0173] Compound 127 (Scheme 21). To a mixture of 4-amino-1-butanol 126(9 g, 100 mmol) and K₂CO₃ (34.5 g, 250 mmol, 2.5 equiv) in 200 ml ofacetonitril was added dropwise methanesulfonyl chloride 96 (6.95 ml,10.3 g, 90 mmol, 3 equiv) in 100 ml of CH₃CN at 0° C. The resultingsolution was stirred at 0° C. for 1 h. The reaction mixture wasflittered and the solvent was evaporated. The residue was purified byflash chromatography on a silica gel column using 50:1 CH₂Cl₂-MeOH as aneluent to give 3.45 g (21%) of the compound 127 as a white powder; ¹HNMR(CDCl₃) δ1.42-1.49 (m, 4H), 2.89 (s, 3H), 2.91 (q, 2H), 3.39 (q, 2H),4.39 (t, 2H), 6.91 (t, 1H ex D₂O); ¹³C NMR (CDCl₃) δ26.1, 29.6, 42.4,60.2, one peak is covered by DMSO-d₆ peaks; MS (ESI) m/z 190.1 (M+Na)⁺(C₅H₁₃NO₃SNa requires 190.2).

[0174] Compound 128 (Scheme 21). Compound 128 was prepared by thesimilar procedure as described above for the compound 125 fromdiclofenac 29 (1.48 g, 5 mmol), compound 127 (0.83 g, 5 mmol), DCC (1.03g, 5 mmol) and DMAP (0.12 g, 1 mmol). The product was purified byrecrystallization from CH₂Cl₂-hexanes to give 1.5 g (67%) of thecompound 128 as a white powder; ¹HNMR (CDCl₃) δ1.57-1.62 (m, 2H),1.70-1.74 (m, 2H), 2.91 (s, 3H), 3.11 (q, 2H), 3.80 (s, 2H), 4.17 (t,2H), 4.44 (t, 1H, ex D²O), 6.54 (d, 1H), 6.87 (bs, 1H, ex D₂O ),6.94-7.00 (m, 2H), 7.12 (t, 1H), 7.23 (t, 1H), 7.34 (d, 2H); ¹³C NMR(CDCl₃) δ25.8, 26.8, 38.8, 40.5, 42.9, 64.7, 118.4, 122.2, 124.3, 124.4,128.2, 129.1, 129.7, 131.1, 137.9, 142.9, 172.5; MS (ESI) m/z 445.3 M⁺(C₁₉H₂₂Cl₂N₂O₄S requires 445.3).

[0175] The synthesis described in Example 54 is outlined in Scheme 22.

EXAMPLE 54

[0176] Compound 130 (Scheme 22). Compound 130 was prepared by thesimilar procedure as described above for the compound 125 fromdiclofenac 29 (1.48 g, 5 mmol), compound 129 (1.22 g, 5 mmol), DCC (1.03g, 5 mmol) and DMAP (0.12 g, 1 mmol). The product was purified byrecrystallization from CH₂Cl₂-hexanes to give 1.3 g (50%) of thecompound 130 as a white powder; ¹H NMR (CDCl₃) δ1.47-1.51 (m, 2H),1.62-1.66 (m, 2H), 2.41 (s, 3H), 2.90-2.94 (q, 2H), 3.77 (s, 2H),4.09(t, 2H), 4.34 (t, 1H, ex D₂O), 6.53 (d, 1H), 6.86 (bs, 1H, ex D₂O ),6.93-7.00 (m, 2H), 7.11(m, 1H), 7.20 (d, 1H), 7.28-7.35 (m, 4H), 7.72(d, 2H); MS (ESI) m/z 544.2 (M+Na)⁺ (C₂₅H₂₆Cl₂N₂O₄SNa requires 544.4).

[0177] The synthesis described in Example 55 is outlined in Scheme 23.

EXAMPLE 55

[0178] Compound 132 (Scheme 23). To a solution of4-(hydroxyphenyl)-1-propanol 131 (3.04 g, 20 mmol) in 20 ml of pyridinewas added compound 115 (15.2 g, 80 mmol, 4 equiv) at 0° C. The resultingsolution was stirred at 0° C. for 2 h and then at rt for another 2 h. Tothe reaction solution was added 200 ml of water. The resulting mixturewas extracted with EtOAc twice. The combined organic phase was washedwith water five times, 0.5N HCl solution once, 5% Na₂CO₃ solution onceand water again. The organic phase was dried (Na₂SO₄) and the solventwas evaporated to give 7.9 g (86%) of the compound 132 as a pale yellowoil; ¹H NMR (CDCl₃) δ1.90 (m, 2H), 2.4 (s, 6H), 2.6 (t, 2H), 3.98 (t,2H), 6.82-6.84 (q, 2H), 6.97 (d, 2H), 7.29-7.34 (q, 4H), 7.68 (d, 2H),7,76 (d, 2H); MS (ESI) m/z 483.3 (M+Na)⁺ (C₂₃H₂₄O₄S₂Na requires 483.5).

[0179] Compound 134 (Scheme 23). A mixture of diclofenac sodium 133(1.59 g, 5 mmol), compound 132 (2.3 g, 5 mmol) and K₂CO₃ (1.38 g, 10mmol) was stirred at rt for 22 h. After reaction, water and EtOAc wereadded and the two layers were separated. The organic phase was washedwith water four times, dried (Na₂SO₄) and concentrated. The residue waspurified by flash chromatography on a silica gel column using 5:1CH₂Cl₂-hexanes as an eluent to give 1.7 g (59%) of the compound 134 as apale yellow oil; ¹H NMR (CDCl₃) δ1.90-1.96 (m, 2H), 2.43 (s, 3H), 2.60(t, 2H), 3.79 (s, 3H), 4.12 (t, 2H), 6.55 (d, 1H), 6.87 (t, 3H),6.94-7.01 (m, 4H), 7.09-7.13 (m, 1H), 7.22-7.35 (m, 5H), 7.69 (d, 2H);¹³C NMR (CDCl₃) δ22.1, 30.4, 31.8, 32.5, 64.8, 118.7, 122.5, 122.7,124.5, 124.8, 128.5, 128.9, 129.3, 129.9, 129.95, 130.1, 131.2, 132.9,138.2, 140.5, 143.1, 145.7, 148.4, 172.7; MS (ESI) m/z 584.3 M⁺(C₃₀H₂₇Cl₂NO₅S requires 584.5¹).

EXAMPLE 56 Reduced Numbers of Intestinal Ulcers in Rat Acute andSubacute Enteropathy Models by the Invention Modified NSAID (Compound19), a Prodrug of Naproxen

[0180] NSAIDs are important drugs used to treat acute and chronicinflammation as well as pain and fever. The major limitation to NSAIDuse is the occurrence of gastrointestinal ulcers and erosions. Theseside effects are produced by a combination of local and systemiceffects. Attempts have been made to circumvent the local side effects ofNSAIDs by making them as prodrugs, which will bypass the stomach, but sofar this has not been clearly successful. It is demonstrated here thatthe invention modified NSAIDs substantially reduce GI toxicity, whileexhibiting dose equivalent efficacy in anti-inflammation activity inboth acute and chronic inflammation animal models.

[0181] Sprague-Dawley rats (male, 150-200 g), were orally dosed oncedaily for either 3 days (acute model) or 14 days (subacute model).Twenty-four hours after the last dose, the rats were injected i.v. withEvans Blue (5 ml/kg, 10 mg/ml) to stain the ulcers. Ten to twentyminutes later the animals were sacrificed by CO2 inhalation and theintestines removed, opened lengthwise and the contents removed. The longdimensions of all ulcers were measured using a ruler and summed to givea total ulcer score.

[0182] In the acute model (FIG. 1), ulceration after dosing with aninvention modified NSAID (compound 19) was 15% of that seen with anequimolar dose of naproxen. PEG had no ulcerogenic effect. In thesubacute model (FIG. 2), ulceration was less than 5% of that seen with acorresponding dose of naproxen at all three doses used. Again, PEG hadno effect. These results suggest that invention modified NSAIDs are muchless ulcerogenic than naproxen.

EXAMPLE 57 Reduction of Chronic Hindlimb Inflammation in the RatAdjuvant Arthritis Model by the Invention Modified NSAID (Compound 19),a Prodrug of Naproxen

[0183] NSAIDs are useful in the treatment of both chronic and acuteinflammatory conditions. Efficacy in chronic inflammation can beestimated using the rat adjuvant arthritis model. In this model Lewismale rats (175-250 g) are injected intradermally in the footpad with M.tuberculosis powder suspended in mineral oil at 5 mg/ml. Progressiveswelling of the uninjected paw and ankle joint between days 5 and 15 ismeasured by plethysmometry.

[0184] Rats were dosed daily by oral gavage with 5 ml/kg of naproxen at3 to 30 mg/kg in phosplate buffered saline (PBS) and with equimolardoses of an invention modified NSAID at 1 ml/kg in PEG 300. The results(FIG. 3) show that the invention modified NSAID resulted inantiinflammatory effects comparable to those of naproxen in this model.

EXAMPLE 58 Reduction of Acute Hindlimb Inflammation in the RatCarrageenan-induced Hindlimb Edema Model by the Invention Modified NSAID(Compound 19) a Prodrug of Naproxen

[0185] Efficacy of NSAIDs in acute inflammation can be estimated byusing intraplantar injection of carrageenan in the rat. Sprague-Dawleyrats (200-250 g male) are injected intradermally in the footpad with 50(1 of a 1% carrageenan solution in PBS. Swelling of the injected paw ismeasured 3 & 4 hours later, using a plethysmometer.

[0186] Pretreatment with oral naproxen one hour before the carrageenaninjection at 10 mg/kg resulted in an approximately 50% reduction inswelling at both time points (Table 1). An equimolar dose of aninvention modified NSAID reduced inflammation to the same degree at bothtime points. These results suggest that invention modified NSAIDs arecomparable in effect to naproxen at 10 mg/kg. TABLE 1 Effects ofnaproxen and the invention modified NSATD (compound 19) on paw volumeincrease in carrageenan- induced inflammation in rats. Treatment 4 Hours5 Hours Vehicle 0.73 ± 0.10 0.85 ± 0.10 Naproxen (1 mg/kg) 0.63 ± 0.070.75 ± 0.08 Naproxen (10 mg/kg)  0.32 ± 0.05*  0.39 ± 0.07* Compound 19(1.75 mg/kg) 0.78 ± 0.04 0.93 ± 0.04 Compound 19 (17.5 mg/kg)  0.34 ±0.06*  0.40 ± 0.06*

[0187] Invention modified NSAIDs are seen to have antiinflammatoryactivity similar to naproxen in the chronic adjuvant arthritis and acutecarrageenan hindlimb edema rat models. The tendency to cause intestinalulcers is reduced substantially inventon modified NSAID. Thus, inventionmodified NSAIDs provide an effective prodrug form of naproxen withreduced intestinal side effects.

EXAMPLE 59 Plasma Pharmacokinetics of Naproxen and the InventionModified NSAID after Oral Administration in Rats

[0188] The invention compound (compound 19) is a naproxen prodrug, whichis a conjugate of naproxen and tosylate. Oral administration of theinvention compound resulted in the release of free naproxen. Thepharmacokinetics of naproxen release from the invention modified NSAIDand its parent drug, naproxen, was evaluated in rats after oraladministration.

[0189] The carotid artery of Sprague-Dawley rat (250-350 g, male) wascatheterized at least one day before drug administration and flushedwith 30% polyvinyl pyrrolidone (PVP) (400 U/mL of heparin) to maintainpatency. At predetermined time points (see Table 2), blood samples (250(L) were collected by unhooking the flushing syringe and letting theblood flow out of the catheter and into the centrifuge tubes. Aftercentrifugation (13,000 rpm, 10 min, 4° C.), the plasma samples werecollected and analyzed in the same day. TABLE 2 Rat group assignment anddoses Test Group Dose* Article # Rat # (mg/kg) Sample Time Naproxen 1 1,2, 3, Oral 5 min, 0.5, 1, 4, 7, 10, & 4 (2 mg/kg) 13, 16, 19, 22, & 24hrs Invention 2 5, 6, 7, Oral 15 min, 0.5, 1, 3, 5, 6, 7, Compound & 8(2 mg/kg) 8, 22, 23, & 24 hrs 19

[0190] Aliquot of plasma sample (100 μL) was mixed with 200 μL ofacetonitrile. After vortexing and centrifugation (13,000 rpm, 10 min, 4°C.), 200 (L of supernatant was removed and added to 300 (L of a 58:42mixture of 50 mM phosphate buffer (pH 5.0) and acetonitrile. Followingvortexing and centrifugation, 25 L of supernatant was removed andanalyzed by HPLC with a UV detection system.

[0191] The average plasma concentration at each time point wascalculated and utilized in a pharmacokinetic analysis. Noncompartmentalpharmacokinetic analysis was carried out using WinNolin (Pharsight,Mountainview, Calif.) to calculate the maximum concentration (C_(max)),time to maximum concentration (T_(max)), area under the curve from zeroto the last time point (AUC_(last)), the area under the curve from zeroto infinite time (AUC_(inf)), and the terminal phase half life(Beta-ti_(1/2)).

[0192] The AUC_(all), AUC_(INF), and t_(1/2) of naproxen from naproxenand a modified form of naproxen according to the invention were found tobe similar (Table 3). On the other hand, for the invention modified formof neproxen, the C_(max) was lower and the T_(max) longer, compared tonaproxen (see Table 3). TABLE 3 Non-Compartmental PharmacokineticAnalysis of naproxen and the invention modified form of naproxenaccording to the (compound 19) after oral administration in rats Dose*C_(max) T_(max) AUC_(all) AUC_(INF) t½ Drug (mg/kg) (μg/mL) (hrs)(μg*hr/mL) (μg*hr/mL) (hrs) N Naproxen 2 7.77 ± 4.13 0.5 ± 0.5 50 ± 6 55± 7 6.2 ± 0.4 4 Invention 2 3.87 ± 1.05 6.8 ± 1.5 49 ± 10 56 ± 14 6.8 ±2.7 4 modified naproxen

[0193] Following oral naproxen administration, the naproxen plasmalevels were at the highest at the first time-point (5 minutes) thendeclined in a bi-exponential manner. In contrast, after oraladministration of a modified form of naproxen according to theinvention, the maximum naproxen levels were observed at a much latertime (T_(max) of 6.8±1.5 hrs). The similar AUC_(all), AUC_(INF), andT_(1/2) values but lower C_(max and longer T) _(max) values supports theconclusions drawn from the results obtained from pharmacologicalstudies, i.e. that a modified form of naproxen according to theinvention conjugate has equivalent pharmacological efficacy and greatlyimproved gastrointestinal safety profile compared to naproxen.

[0194] While the invention has been described in detail with referenceto certain preferred embodiments thereof, it will be understood thatmodifications and variations are within the spirit and scope of thatwhich is described and claimed.

What is claimed is:
 1. A compound having the structure: X—L—Z wherein:X=a non-steroidal anti-inflammatory drug (NSAID), L=an optionallinker/spacer, Z=a sulfur-containing functional group.
 2. A compoundaccording to claim 1 wherein said NSAID is acetaminophen, aspirin,ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac,diflunisal, etodolac, fenprofen calcium, flurobiprofen, indomethacin,ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesiumsalicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam,sodium salicylate, sulindac, tolmetin, meloxicam, nabumetone, naproxen,lomoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenicacid, or flosulide.
 3. A compound according to claim 2 wherein saidNSAID is naproxen, aspirin, ibuprofen, flurbiprofen, indomethacin,ketoprofen, or carprofen.
 4. A compound according to claim 1 wherein Zhas the structure: —Y—S(O)_(n)—Y′—Q wherein: each of Y and Y′ areoptionally present, and when present are independently —O—, —S— or—NR′—, wherein R′ is H or an optionally substituted hydrocarbyl moiety;n is 1 or 2, and Q is H, a metal cation or an optionally substitutedhydrocarbyl moiety.
 5. A compound according to claim 1 wherein thesulfur-containing functional group is sulfonate, reverse sulfonate,sulfonamide, reverse sulfonamide, sulfone, sulfoxide, sulfinate, orreverse sulfinate.
 6. A compound according to claim 5 wherein thesulfur-containing functional group is sulfonate or reverse sulfonate. 7.A compound according to claim 6 wherein the sulfur-containing functionalgroup is a nitro, nitrate, nitrite, nitrosothiol, nitroglyceryl,S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinylsubstituted aromatic sulfonate.
 8. A compound according to claim 7wherein said aromatic sulfonate is tosylate or brosylate.
 9. A compoundaccording to claim 6 wherein the sulfur-containing functional group is anitro, nitrate, nitrite, nitrosothiol, nitroglyceryl,S-nitrosocysteinyl, S-nitrosoglutathionyl, oxime or N-hydroxyguanidinylsubstituted C1 to C10 alkyl sulfonate.
 10. A compound according to claim9 wherein the alkyl sulfonate is mesylate or triflate.
 11. A compoundaccording to claim 5 wherein the sulfur-containing functional group is asulfone.
 12. A compound according to claim 11 wherein thesulfur-containing functional group is a nitro, nitrate, nitrite,nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl,oxime or N-hydroxyguanidinyl substituted C₁ to C₁₀ alkyl sulfone.
 13. Acompound according to claim 12 wherein said sulfone is methyl sulfone,ethyl sulfone.
 14. A compound according to claim 11 wherein thesulfur-containing functional group is a nitro, nitrate, nitrite,nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl,oxime or N-hydroxyguanidinyl substituted aromatic sulfone.
 15. Acompound according to claim 14 wherein the sulfur-containing functionalgroup is a p-substituted aromatic sulfone.
 16. A compound according toclaim 5 wherein the sulfur-containing functional group is a sulfonamideor reverse sulfonamide.
 17. A compound according to claim 16 wherein thesulfur-containing functional group is a nitro, nitrate, nitrite,nitrosothiol, nitroglyceryl, S-nitrosocysteinyl, S-nitrosoglutathionyl,oxime or N-hydroxyguanidinyl substituted C₁ to C₁₀ alkyl sulfonamide.18. A compound according to claim 17 wherein the sulfur-containingfunctional group is methyl sulfonamide.
 19. A compound according toclaim 16 wherein the sulfur-containing functional group is a nitro,nitrate, nitrite, nitrosothiol, nitroglyceryl, S-nitrosocysteinyl,S-nitrosoglutathionyl, oxime or N-hydroxyguanidinyl substituted aromaticsulfonamide.
 20. A compound according to claim 19 wherein thesulfur-containing functional group is toluene sulfonamide.
 21. Acompound according to claim 5 wherein the sulfur-containing functionalgroup is a sulfinate or reverse sulfinate.
 22. A compound according toclaim 1 wherein L, when present, has the structure: W—R— wherein: R isoptional, and when present is alkylene, substituted alkylene,cycloalkylene, substituted cycloalkylene, heterocyclic, substitutedheterocyclic, oxyalkylene, substituted oxyalkylene, alkenylene,substituted alkenylene, arylene, substituted arylene, alkarylene,substituted alkarylene, aralkylene or substituted aralkylene, and W isester, reverse ester, thioester, reverse thioester, amide, reverseamide, phosphate, phosphonate, imine or enamine.
 23. A formulationcomprising a compound according to claim 1 in a pharmaceuticallyacceptable carrier therefor.
 24. A formulation according to claim 23wherein said pharmaceutically acceptable carrier is a solid, solution,emulsion, dispersion, micelle or liposome.
 25. A formulation accordingto claim 23 wherein said pharmaceutically acceptable carrier furthercomprises an enteric coating.
 26. A method for the alleviation of sideeffects induced by the administration of a non-steroidalanti-inflammatory drug (NSAID) to a subject, said method comprisingchemically modifying said NSAID prior to administration to a subject,wherein said NSAID is chemically modified by covalent attachment theretoof a sulfur-containing functional group.
 27. A method for alleviatingthe systemic toxicity of a non-steroidal anti-inflammatory drug (NSAID),said method comprising chemically modifying said NSAID prior toadministration to a subject, wherein said NSAID is chemically modifiedby covalent attachment thereto of a sulfur-containing functional group.28. A method for reducing the maximum concentration in plasma achievedupon administration of a non-steroidal anti-inflammatory drug (NSAID),said method comprising modifying the NSAID by covalent attachmentthereto of a sulfur-containing functional group.
 29. A method for thecontrolled release in vivo of a non-steroidal anti-inflammatory drug(NSAID), said method comprising chemically modifying the NSAID by thecovalent attachment thereto of a sulfur-containing functional group. 30.A method for the treatment of a subject afflicted with a pathologicalcondition, said method comprising administering to said subject atherapeutically effective amount of a chemically modified non-steroidalanti-inflammatory drug (NSAID), wherein the NSAID is effective fortreatment of said condition, and wherein the modified NSAID is preparedby covalent attachment thereto of a sulfur-containing functional group.31. In a method for the administration of a non-steroidalanti-inflammatory drug (NSAID) to a subject for the treatment of apathological condition, the improvement comprising directly orindirectly covalently attaching said NSAID to a sulfur-containingfunctional group prior to administration thereof to said subject.
 32. Amethod for the preparation of a modified non-steroidal anti-inflammatorydrug (NSAID) having reduced propensity to induce side effects, saidmethod comprising modifying the NSAID by directly or indirectlycovalently attaching said NSAID to a sulfur-containing functional groupprior to administration thereof to said subject.
 33. In the treatment ofa subject suffering from a pathological condition by administrationthereto of a non-steroidal anti-inflammatory drug (NSAID), theimprovement comprising covalently attaching said NSAID to asulfur-containing functional group prior to administration thereof tosaid subject.
 34. A method for the preparation of a protected form of anon-steroidal anti-inflammatory drug (NSAID), said method comprisingdirectly or indirectly covalently attaching a sulfur-containingfunctional group to said NSAID.
 35. A method for reducing the sideeffects induced by administration of a non-steroidal anti-inflammatorydrug (NSAID) to a subject, said method comprising directly or indirectlycovalently attaching a sulfur-containing functional group to said NSAIDprior to administration to said subject.
 36. A method for enhancing theeffectiveness of a non-steroidal anti-inflammatory drug (NSAID), saidmethod comprising directly or indirectly covalently attaching asulfur-containing functional group to said NSAID.
 37. A method for theprevention or treatment of an inflammatory or infectious disease in asubject in need thereof, said method comprising administering to saidsubject an amount of the compound of claim 1 effective to alleviate saidcondition.